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Chronic, Intermittent Microdoses of the Psychedelic N,N-Dimethyltryptamine (DMT) Produce Positive Effects on Mood and Anxiety in Rodents

  • Lindsay P. Cameron
    Lindsay P. Cameron
    Neuroscience Graduate Program, University of California, Davis, 1544 Newton Ct, Davis, California 95618, United States
    More by Lindsay P. Cameron
  • , 
  • Charlie J. Benson
    Charlie J. Benson
    Department of Chemistry, University of California, Davis, One Shields Avenue, Davis, California 95616, United States
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  • , 
  • Brian C. DeFelice
    Brian C. DeFelice
    West Coast Metabolomics Center, University of California, Davis, One Shields Avenue, Davis, California 95616, United States
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  • , 
  • Oliver Fiehn
    Oliver Fiehn
    West Coast Metabolomics Center, University of California, Davis, One Shields Avenue, Davis, California 95616, United States
    Biochemistry Department, King Abdulaziz University, Jeddah, Saudi-Arabia
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    Orcidhttp://orcid.org/0000-0002-6261-8928
  • , and 
  • David E. Olson*
    David E. Olson
    Department of Chemistry, University of California, Davis, One Shields Avenue, Davis, California 95616, United States
    Department of Biochemistry & Molecular Medicine, School of Medicine, University of California, Davis, 2700 Stockton Blvd, Suite 2102, Sacramento, California 95817, United States
    Center for Neuroscience, University of California, Davis, 1544 Newton Ct, Davis, California 95618, United States
    *E-mail: [email protected]
    More by David E. Olson
    Orcidhttp://orcid.org/0000-0002-4517-0543
Cite this: ACS Chem. Neurosci. 2019, 10, 7, 3261–3270
Publication Date (Web):March 4, 2019
https://doi.org/10.1021/acschemneuro.8b00692

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Abstract

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Drugs capable of ameliorating symptoms of depression and anxiety while also improving cognitive function and sociability are highly desirable. Anecdotal reports have suggested that serotonergic psychedelics administered in low doses on a chronic, intermittent schedule, so-called “microdosing”, might produce beneficial effects on mood, anxiety, cognition, and social interaction. Here, we test this hypothesis by subjecting male and female Sprague Dawley rats to behavioral testing following the chronic, intermittent administration of low doses of the psychedelic N,N-dimethyltryptamine (DMT). The behavioral and cellular effects of this dosing regimen were distinct from those induced following a single high dose of the drug. We found that chronic, intermittent, low doses of DMT produced an antidepressant-like phenotype and enhanced fear extinction learning without impacting working memory or social interaction. Additionally, male rats treated with DMT on this schedule gained a significant amount of body weight during the course of the study. Taken together, our results suggest that psychedelic microdosing may alleviate symptoms of mood and anxiety disorders, though the potential hazards of this practice warrant further investigation.

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SPECIAL ISSUE

This article is part of the Serotonin Research 2018 special issue.

Introduction

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Mood and anxiety disorders are among the leading causes of disability worldwide, (1,2) and antidepressants remain one of the most highly prescribed medications in the United States. (3) Current therapeutic strategies for treating these disorders are slow-acting and prove to be ineffective for many patients. (4) Thus, there is a critical need to develop new treatment strategies for these disorders.
Serotonergic psychedelics, such as lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT), have a long history of use as experimental therapeutics in the clinic for treating depression, anxiety, and substance use disorder. (5−10) However, it is unclear whether hallucinogenic doses of these drugs are required for them to produce therapeutic effects. Psychedelic microdosing—the practice of administering subhallucinogenic doses of psychedelic compounds on a chronic, intermittent schedule—is rapidly gaining popularity due to its alleged antidepressant and anxiolytic effects. (11−13) Despite the prevalence of psychedelic microdosing, there are essentially no peer-reviewed studies that have investigated the potential benefits and risks of this practice. (14,15)
Psychedelics are potent psychoplastogens, (16) and their effects on neural plasticity have been invoked to explain their long-lasting behavioral effects related to mood and anxiety. (17) Previously, we observed that even a low dose of DMT caused changes in the frequency and amplitude of spontaneous excitatory postsynaptic currents (EPSCs) in the prefrontal cortex (PFC) of rats that lasted long after the drug had been cleared from the body. (16) Therefore, we hypothesized that administration of this low dose on a chronic, intermittent schedule might impact behaviors relevant to mood and anxiety that involve the PFC. (18−23)
Here, we demonstrate that chronic (∼2 months), intermittent (every third day), low (1 mg/kg) doses of DMT facilitate fear extinction learning and reduce immobility in the forced swim test without producing the anxiogenic-like effects characteristic of a high dose (10 mg/kg). (24) However, the former dosing regimen also significantly increases bodyweight in male rats. Taken together, the data presented here suggest that subhallucinogenic doses of psychedelic compounds might possess value for treating and/or preventing mood and anxiety disorders. Despite the therapeutic potential of psychedelic microdosing, this practice is not without risks, and future studies need to better define the potential for negative neurobiological or metabolic repercussions.

Results

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Experimental Design for Assessing the Effects of Chronic, Intermittent, Low Doses of DMT on Rat Behaviors

Anecdotal human reports regarding psychedelic microdosing were informative when designing our rodent studies. First, young adults appear to be the most likely to practice psychedelic microdosing, so we employed similarly aged rats (i.e., postnatal day 56) in our study. Both male and female rats were used. Animals were treated every third day for 2 weeks before beginning behavioral testing (Figure 1), and drug administration continued on this schedule throughout the remainder of the study. Behavioral experiments were generally ordered from least to most stressful, included a variety of tests relevant to mood, anxiety, and cognitive function, and were completed during the 2 day period between administration of doses to ensure that any effects observed were due to persistent neural adaptations as opposed to the acute effects of the drug. Following the completion of behavioral testing, the animals were subjected to metabolic monitoring and sacrificed. Tissue was collected and subjected to additional structural and biochemical analyses.

Figure 1

Figure 1. Experimental design for testing the effects of chronic, intermittent, low doses of DMT on rats. Blue boxes indicate the days when drug was administered. Behavioral testing was performed on the days between doses. Gray boxes indicate days the animals spent in their home cages with no testing being performed. CLAMS = Comprehensive Lab Animal Monitoring System.

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We decided to use the psychedelic N,N-dimethyltryptamine (DMT) in our studies for several reasons. First, DMT constitutes the core structure of all indole-containing psychedelics including LSD and psilocybin. (10) Second, DMT is known to impact rodent behaviors relevant to mood, anxiety, cognitive function, and sociability. (10,25−31) Third, DMT is the principal psychoactive component in ayahuasca, an Amazonian tisane typically administered on a chronic, intermittent schedule that has been shown to have antidepressant effects. (10) Additionally, we have previously demonstrated that an acute hallucinogenic dose of DMT (10 mg/kg) administered to rats produces robust behavioral phenotypes in several paradigms relevant to mood and anxiety disorders, enabling us to compare the effects of a single high dose of the compound to those produced by chronic, intermittent, low doses of the drug. While there is no well-established definition of what constitutes a “microdose”, humans typically employ 1/10 of a hallucinogenic dose, (11) so we opted to administer DMT at 1 mg/kg, or 1/10 of the dose used in our acute study. (24)
Several pieces of evidence suggest that a 1 mg/kg dose of DMT is subhallucinogenic in rats. First, 1 mg/kg DMT only produces ∼20% correct lever responding in Sprague Dawley rats trained to discriminate DMT from saline. (32) Additionally, this dose only produces approximately 10–20% drug-appropriate responding in Sprague Dawley rats trained to discriminate other hallucinogens such as (−)-2,5-dimethoxy-4-methylamphetamine (DOM, 0.5 mg/kg) or LSD (0.1 mg/kg) from saline. (32) Furthermore, a 1 mg/kg dose of DMT does not produce the drastic change in body posture that is characteristic of a 10 mg/kg dose. (24) Finally, the 1 mg/kg dose is predicted to be subhallucinogenic in rats based on allometric scaling (33) of known subhallucinogenic doses in humans. (34) In these human studies, DMT was administered intravenously, a route that avoids first-pass metabolism and yields a high maximum concentration in the brain. We chose to administer DMT to rats via intraperitoneal injection reasoning that drug administered by this route is slower to enter the bloodstream and more susceptible to hepatic metabolism than intravenous administration, (35) thus providing additional assurance that the dose selected for our study would be subhallucinogenic.
Prior to our study, essentially nothing was known about the effects of psychedelic microdosing on animal behaviors. Therefore, our primary goal was to determine which behavioral tests were likely to be impacted by this dosing regimen. We chose to use the highest dose still considered to be subhallucinogenic, reasoning that it should produce the maximal effect with lower doses expected to be less efficacious.

Chronic, Intermittent, Low Doses of DMT Do Not Produce Anxiogenic-like Effects in NIL or EPM Tests

To assess the effects of chronic, intermittent, low doses of DMT on anxiety levels, animals were tested in both novelty-induced locomotion (NIL) and the elevated plus maze (EPM) paradigms. Following exposure to a novel open space, we measured the total distance traveled, degree of thigmotaxis, number of rearings, and time spent rearing (Figure S1a). Using a Z-normalization procedure developed by Guilloux and co-workers, (36) we combined all of these related measures into a single NIL Score. No statistical difference between the male and female treatment groups was observed, so these data were combined (Figure 2a). Chronic, intermittent, low doses of DMT did not produce a significant difference between treatment groups in the NIL Score (p = 0.08), though DMT trended toward producing an anxiolytic-like effect.

Figure 2

Figure 2. Chronic, intermittent, low doses of DMT do not produce anxiogenic-like effects in rats. (a) DMT-treated and vehicle-treated groups display similar phenotypes in the NIL (a) and EPM (b) paradigms. Error bars represent SEM, ns = not significant. See Supplementary Table 1 for details of all statistical tests.

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As in the open field, DMT-treated animals did not display any behavioral signs of anxiety in the EPM as determined by the percentage of time spent in either the open or closed arms of the maze or the number of open or closed arm entries (Figure S1b). Again, these related measures were Z-normalized and combined into a single EPM Score. As no statistical difference between the male and female treatment groups was observed, these data were combined (Figure 2b). Animals treated with DMT were indistinguishable from vehicle controls (p = 0.92). Additionally, the treatment groups displayed similar levels of locomotion in the EPM maze as determined by total distance traveled and average velocity (Figure S1c). This distinct lack of any anxiogenic-like effect in either the NIL or EPM demonstrates a striking difference between the chronic, intermittent, low dose and the single high dose psychedelic treatment paradigms, as a single high dose of DMT is known to produce robust anxiogenic-like effects in both the NIL and EPM behavioral tests. (24)

Chronic, Intermittent, Low Doses of DMT Facilitate Cued Fear Extinction Learning

Both contextual and cued fear memory were assessed following fear conditioning (Figure 3a). Prior to receiving foot shocks, there was no difference in baseline freezing levels between the vehicle- and DMT-treated groups (Figure 3b). Similarly, the treatment groups were indistinguishable immediately after the last training foot shock (Figure 3c). Again, this latter point highlights the drastic differences between a chronic, intermittent, low dose paradigm and a single high dose of DMT, as the latter significantly increases freezing levels immediately following foot shocks. (24)

Figure 3

Figure 3. Chronic, intermittent, low doses of DMT enhance fear extinction in rats. (a) Experimental design for the fear conditioning and extinction experiments. (b, c) DMT- and vehicle-treated groups displayed comparable levels of freezing in the 2 min period before (b) and after (c) receiving foot shocks. (d, e) Neither contextual fear memory (d) nor cued fear memory (e) were impaired by chronic, intermittent treatment with low doses of DMT. (f) DMT-treated animals exhibited enhanced cued extinction memory as compared to vehicle-treated controls. n = 11 DMT-treated animals (5 male and 6 female), n = 12 vehicle-treated animals (6 male and 6 female); error bars represent SEM, ns = not significant, *p < 0.05. See Supplementary Table 1 for details of all statistical tests.

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The day after fear conditioning, contextual fear memory was assessed in the original training context. Freezing behavior was comparable between the groups indicating no effect of treatment on contextual fear memory (Figure 3d). The following day, animals were administered DMT or vehicle and allowed to rest in their home cages. The next day, animals were placed in a new context and presented the auditory conditioned stimulus multiple times. Again, freezing levels were indistinguishable between the two groups demonstrating that treatment did not impair the formation of cued fear memories (Figure 3e). This cued memory test also served as the extinction training. After 24 h, the cued memory test was repeated, however, the DMT-treated animals froze significantly less than the vehicle controls (p = 0.03), suggesting that chronic, intermittent, low doses of DMT facilitate fear extinction learning (Figure 3f).

Chronic, Intermittent, Low Doses of DMT Elicit Antidepressant-like Responses in the Forced Swim Test (FST)

To determine if this treatment regimen also produces antidepressant-like effects in rodents, rats were subjected to a 2 day modified forced swim paradigm consisting of a pretest on the first day and a test swim 24 h later. Both male and female rats treated with low doses of DMT on a chronic, intermittent schedule displayed robust antidepressant-like responses when compared to the vehicle-treated controls (Figure 4), with both males and females exhibiting similar behavior. Treatment significantly decreased immobility for females (p = 0.02), and though not significant after controlling for multiple hypothesis testing, a similar trend was observed for males. When individual sex/treatment pairs were analyzed via one-way analysis of variance (ANOVA) with Tukey’s post hoc test, there were no statistical differences in climbing or swimming behavior between sexes or treatment groups, so the data were combined. When males and females were analyzed together, a significant effect of treatment on swimming behavior (p = 0.04) was observed. Similarly, DMT treatment trended toward producing an antidepressant-like effect on climbing behavior (p = 0.05) as well. Because this dosing regimen does not increase locomotion in the open field (Figure S1a), in the EPM (Figure S1c), or in a novel fear conditioning chamber prior to receiving foot shocks (Figure 3b), this response cannot be attributed to a general increase in activity.

Figure 4

Figure 4. Chronic, intermittent, low doses of DMT produce antidepressant-like effects in rats. Such effects include reduced immobility (a), increased climbing (b), and increased swimming (c) in the FST. Error bars represent SEM, ns = not significant, *p < 0.05. See Supplementary Table 1 for details of all statistical tests.

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Unlike the effects observed in the NIL and EPM paradigms, both the enhanced fear extinction learning and antidepressant-like effects in the FST following chronic, intermittent DMT treatment are consistent with the acute effects of a single high dose of DMT. Moreover, these data represent the first experiments in rodents corroborating the antidepressant and anxiolytic effects of psychedelic microdosing reported by humans.

Chronic, Intermittent, Low Doses of DMT Have No Effect on Working/Short-Term Memory or Social Interaction

In addition to positive effects on mood and anxiety, humans also report that psychedelic microdosing can improve various aspects of cognitive function and increase sociability. To assess the effects of chronic, intermittent, low doses of DMT on working memory in rodents, we took advantage of continuous spontaneous alternation behavior (SAB). (37) In this paradigm, rodents are allowed to freely explore a T-maze and the number of successive and total arm entries are recorded. In the absence of a reinforcing stimulus (positive or negative), the natural foraging behavior of the animal is to avoid the most recently entered arm after reaching the central node of the maze. Deficits in attention and spatial working memory typically manifest as reductions in percent alternation, however, the animals microdosed with DMT were indistinguishable from vehicle controls (Figure S2a). Moreover, they exhibited similar levels of locomotion as measured by the total number of arm entries (Figure S2b).
Next, we assessed short-term memory in the absence of aversive or appetitive conditioning using novel object recognition (NOR). (38) No differences were observed between the treatment groups with respect to the total amount of time spent interacting with the familiar vs the novel object (Figure S2c) or the discrimination index (Figure S2d). Similar results were observed for both male and females in the SAB and NOR paradigms.
Finally, we determined the impact of chronic, intermittent, low doses of DMT on sociability using the three-chambered social approach paradigm. (39) Social preference was observed for both the vehicle- and DMT-treated groups, but there was no difference between the groups with respect to the amount of time that they spent interacting with either a novel drug-naïve conspecific or a novel inanimate object (Figure S2e). Taken together, our data demonstrate that chronic, intermittent low doses of DMT do not produce any obvious impairments in working/short-term memory or social interaction in rodents. However, unlike rodent tests of anxiety and depression (Figures 3 and 4), these rodent tests of cognitive function and sociability do not corroborate the beneficial effects of psychedelic microdosing reported by humans.

Chronic, Intermittent, Low Doses of DMT Decrease Dendritic Spine Density in the PFC of Female, but Not Male, Rats

As a single high dose of DMT increases dendritic spine density in the prefrontal cortex (PFC), (16) we assessed the effect of chronic, intermittent low doses of DMT on spine density in that brain region. Following 7 weeks of microdosing and behavioral testing (Figure 1), animals were sacrificed and the structure of layer V pyramidal neurons in the PFC were assessed via Golgi–Cox staining. We observed comparable spine density in the PFC of both the vehicle- and DMT-treated male animals (p = 0.98) (Figure 5). However, DMT-treated females showed a significant decrease in the number of spines per 10 μm as compared to vehicle controls (p = 0.03).

Figure 5

Figure 5. Chronic, intermittent, low doses of DMT decrease dendritic spine density in the PFC of female, but not male, rats. (a) Dendritic spine density on layer V pyramidal neurons is reduced following psychedelic microdosing in females (DMT n = 20 cells from 2 animals; VEH n = 20 cells from 2 animals), but not males (DMT n = 12 cells from 2 animals; VEH n = 21 cells from 2 animals) as measured via Golgi–Cox staining. (b) Representative images of Golgi–Cox stained layer V pyramidal neurons in the PFC of rats. M = males, F = females, Error bars represent SEM, ns = not significant, *p < 0.05. See Supplementary Table 1 for details of all statistical tests.

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Chronic, Intermittent, Low Doses of DMT Do Not Change Gene Expression in the PFC

In addition to assessing structural changes in the PFC, we also determined if chronic, intermittent, low doses of DMT impacted expression of several key genes (Figure 6). First, we assessed the expression of EGR1, EGR2, ARC, and FOS via droplet digital PCR (ddPCR), as acute doses of psychedelics are known to increase their expression. (40) Chronic, intermittent, low doses of DMT did not alter the expression of any of these genes. Furthermore, it did not increase the expression of BDNF, a result that contrasts with increased BDNF expression observed in the cortex of rats following both acute (41) and chronic administration (42) of high doses of psychedelics. Finally, HTR2A gene expression was unchanged despite chronic stimulation of the 5-HT2A receptor for nearly 2 months.

Chronic, Intermittent, Low Doses of DMT Impact Metabolism

Over the course of the 7 week study, we noticed that DMT-treated male rats, but not females, gained significantly more bodyweight than their vehicle-treated counterparts (p = 0.003 and 0.99, respectively) (Figure S3a and b). The weights of vehicle-treated male rats increased by 165%, while those of DMT-treated male rats increased by 182% (Figure S3b). Therefore, we subjected the rats to metabolic monitoring for ∼48 h in isolation using a Comprehensive Lab Animal Monitoring System (CLAMS) following completion of behavioral testing (Figure 1). Despite gaining more weight, DMT-treated animals trended toward consuming less food than vehicle controls (Figure S3c). These results could not be easily explained by changes in activity or energy expenditure as horizontal movement, vertical movement, heat dissipated, and respiratory exchange rate (RER) were not statistically different between the treatment groups (Figure S3d–g).
Next, we replicated the DMT microdosing experiment using a larger cohort of male rats without performing any behavioral testing. As observed previously, male rats administered intermittent, low doses of DMT over the course of 1 month gained weight at a faster rate than the vehicle-treated controls (Figure S4a; p = 0.03, two-way repeated measures ANOVA). Divergence between the two groups could be observed as early as 1 week following the initiation of the experiment. After 4 weeks, the animals were sacrificed and their fat pads were dissected and quantified as a percentage of total body weight (Figure S4b). No differences were observed between treatment groups with respect to either white (epidydimal, mesenteric, retroperitoneal, subcutaneous) or brown adipose tissue, suggesting that DMT-induced weight increases do not simply reflect increased adiposity.
In an attempt to shed some light on the metabolic changes induced by chronic, intermittent, low doses of DMT, we measured steroid levels in serum samples from the DMT-treated animals previously subjected to behavioral testing using mass spectrometry-based metabolomics profiling (Supplementary Table 2). As expected, principal components analysis revealed large sex differences in steroid profiles (Figure S5b). However, DMT treatment appeared to have little overall effect (Figure S5c and d), and after controlling for multiple hypothesis testing, there were no statistical differences between the treatment groups.

Discussion

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Several clinical studies have demonstrated that acute, hallucinogenic doses of psychedelic compounds can produce rapid, long-lasting changes in mood and behavior in humans. (43−45) Recent data also suggests that a single hallucinogenic dose of DMT can change rodent brain structure and behavior long after the drug has been cleared from the body. (16,24) Furthermore, we previously demonstrated that a nonhallucinogenic 1 mg/kg dose of DMT leads to increased frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) in layer V pyramidal neurons of the PFC 24 h after administration. (16) Therefore, we hypothesized that administering DMT on a chronic, intermittent, low dose regimen—similar to psychedelic microdosing—might alter behavior.
To the best of our knowledge, there has only been one peer-reviewed scientific report on the effects of psychedelic microdosing in rodents. This study employed three doses of psilocin spaced over 6 days, with behavioral testing occurring 48 h after the final dose. (46) In agreement with our findings, the authors report no statistically significant changes in EPM behavior when two-tailed statistical tests were employed. The distinct lack of robust anxiogenic-like effects following chronic, intermittent, low doses of psychedelics is striking when compared to the effects of acute high doses. A hallucinogenic dose of DMT (10 mg/kg) decreases exploratory behavior in the NIL paradigm (i.e., both locomotion and rearing), decreases the number of open arm entries in the EPM, and increases freezing behavior immediately following the administration of foot shocks. (24) None of these effects are observed when a subhallucinogenic dose (1 mg/kg) of DMT is administered on a chronic intermittent schedule (Figures 2 and 3c).
Unlike the anxiogenic-like effects produced by an acute hallucinogenic dose of DMT, the beneficial effects on fear extinction learning and forced swim behavior (24) are reproduced by the chronic, intermittent low dose regimen (Figures 3f and 4). These antidepressant-like and anxiolytic-like effects are consistent with the anecdotal human reports regarding psychedelic microdosing providing strong supporting evidence that psychedelic microdosing might actually have therapeutic potential. Compounds capable of enhancing fear extinction learning in rodents, such as 3,4-methylenedioxymethamphetamine (MDMA), (47,48) are excellent candidates for treating PTSD symptoms in humans.
We hypothesize that chronic, intermittent low doses of DMT increase the excitability of pyramidal neurons in the PFC that project to the basolateral amygdala and dorsal raphe nucleus to decrease the expression of conditioned fear responses and increase swimming behavior in the forced swim test, respectively. DMT and other psychedelics are potent psychoplastogens—compounds capable of promoting the rapid growth of dendritic branches, spines, and synapses—due to their ability to stimulate the mammalian target of rapamycin (mTOR) through activation of 5-HT2A receptors. (16) These receptors are enriched in the prefrontal cortex, an area of the brain that is known to exert top-down control over mood and anxiety. It is likely that the behavioral changes induced by chronic, intermittent low doses of DMT are the result of positive neuroadaptations in circuits involving the PFC that are relevant to fear extinction (22) and effortful response to behavioral challenge (i.e., FST) (21) as DMT has an extremely short half-life in rats (ca. 15 min) (49) and the behaviors were performed on days when DMT was NOT administered. In fact, we have previously shown that a 1 mg/kg dose of DMT increases the frequency and amplitude of spontaneous EPSCs in the PFC long after DMT had been cleared from the body. (16)
Despite producing similar anxiolytic-like and antidepressant-like behavioral effects, an acute hallucinogenic dose and chronic, intermittent, low doses of DMT produce very different biochemical and structural phenotypes. We have previously shown that a single hallucinogenic dose of DMT (10 mg/kg) increases dendritic spine density on pyramidal neurons of the PFC, (16) but a similar effect was not observed following administration of chronic, intermittent low doses (1 mg/kg) of DMT (Figure 5). We hypothesize that chronic, intermittent low doses of DMT promote sufficient plasticity to strengthen key circuits involved in the regulation of mood and fear, thus impacting behavior, but that homeostatic plasticity tightly controls the overall synaptic input to these neurons leading to similar spine densities between treatment groups over time.
While there were no major behavioral differences between male and female rats following DMT treatment, there were distinct changes in neuronal structure. Dendritic spine density on pyramidal neurons of the PFC was unchanged in male rats administered chronic, intermittent, low doses of DMT; however, female rats exhibited a reduction in spine density (Figure 5). As psychedelics are known to increase glutamate release in the cortex, (50) the reduced spine density observed in females could reflect greater sensitivity to glutamatergic excitotoxicity. This highlights the fact that the overall psychedelic microdosing load, which includes the amount of drug in each dose, the frequency of administration, and the length of treatment, is likely to be critical for achieving the beneficial effects of psychedelic microdosing without negative repercussions. Long-term intermittent use of ayahuasca is correlated with thinning of the posterior cingulate cortex (PCC) in humans, (51) but not increased risk for mental illness. (52) However, Nichols and co-workers have shown that chronic (>3 months), intermittent, high doses of LSD administered to rats produce neuroadaptations leading to a persistent behavioral state consisting of hyperactivity, anhedonia, and social deficits. (53) These behavioral changes are accompanied by significant gene expression changes in the PFC related to neural plasticity. (35) As a similar dose of LSD given over 11 days resulted in antidepressant-like effects, (54) it appears that the total length of treatment is critical for determining behavioral outcomes.
A single hallucinogenic dose of several psychedelic compounds has been shown to increase gene expression of several genes related to neural plasticity. (55,56) However, we did not observe similar changes following the administration of chronic, intermittent low doses of DMT (Figure 6). Duman and co-workers also observed that repeated dosing of 2,5-dimethoxy-4-iodoamphetamine (DOI), an amphetamine-based psychedelic, caused minimal changes in BDNF expression in the cortex when compared to a single acute dose. They hypothesized that 5-HT2 downregulation might explain the differences observed between the two dosing regimens. However, in the case of chronic, intermittent administration of low dose DMT, we do not observe any changes in HTR2A expression (Figure 6), and it has been previously shown that DMT does not induce receptor downregulation in cellular studies, (57) nor does it cause tolerance in humans. (58) This distinct lack of increased BDNF expression following chronic, intermittent, low doses of DMT highlights an important mechanistic difference between psychedelic microdosing and chronic treatment with selective serotonin reuptake inhibitors and other slow-acting antidepressants. In the latter case, increased BDNF expression is believed to facilitate the repair of damaged circuits relevant to mood and anxiety. (59) Chronic, intermittent low doses of DMT appear to accomplish this without any obvious changes in the expression of BDNF or other genes known to be differentially regulated following administration of a single high dose of a psychedelic.

Figure 6

Figure 6. Chronic, intermittent, low doses of DMT produce minimal effects on gene expression in the PFC of rats. Gene expression studies (ddPCR) from rat PFC tissue indicate that psychedelic microdosing produces minimal effects on gene expression (n = 5 females and 3–5 males per group). To account for multiple hypothesis testing, a Bonferroni correction was made such that the α = 0.05/6 comparisons = 0.0083 for this family of experiments. Error bars represent SEM, ns = not significant. See Supplementary Table 1 for details of all statistical tests.

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In addition to neurobiologial effects, psychedelic microdosing might also impact metabolism. After correcting for multiple hypothesis testing, male rats administered chronic, intermittent low doses of DMT exhibited a trend toward eating less food (p = 0.13, Figure S3c). Similar effects have been observed following administration of ayahuasca (60) and various serotonergic agonists. (61) Surprisingly, despite eating less food than vehicle-treated controls, the DMT-treated animals gained significantly more weight (Figure S3b). This contrasted with a previous report of chronic ayahuasca administration in rats, (60) and the reason for the discrepancy is not immediately obvious. Metabolomics experiments revealed that serum levels of most steroids remained unchanged following psychedelic microdosing. However, male rats treated with DMT did experience a nearly 50% reduction in estradiol levels, though the effect was not significant after correcting for multiple hypothesis testing.
In general, more work needs to be done to identify potential risks associated with the increasingly popular practice of psychedelic microdosing. While psychedelic-induced activation of mTOR in young adults might lead to changes in neural plasticity having beneficial effects on mood and anxiety, in some individuals, psychedelic microdosing could cause overstimulation of cortical neurons and actually exacerbate symptoms of neuropsychiatric disorders. Moreover, nothing is known about the effects of psychedelic microdosing on neurodevelopment or the aging brain. As overactivation of mTOR has been proposed to contribute to the development of autism spectrum disorder (ASD) (62) and Alzheimer’s disease (AD), (63) more research is warranted to fully understand the risks associated with the chronic, intermittent use of psychedelics and related psychoplastogens.
While our study only assessed the impact of a single low dose of DMT administered on a chronic, intermittent schedule, it is important because it provides critical information about which behaviors are sensitive to psychedelic microdosing, and which are not, for both males and females. Moreover, it accomplished this using the minimal number of animals possible—an important ethical consideration. Follow-up studies can now hone in on particular behaviors of interest (e.g., FST or fear extinction) and perform dose–response or time–response studies. We still do not know if (1) lower doses would maintain therapeutic efficacy while minimizing changes in spine density or other potential side effects, or (2) if more complex dose–response relationships (e.g., U-shaped) are operative. Future studies examining dose–response effects and the impact of different dosing schedules are certainly warranted.
Despite the potential risks associated with psychedelic microdosing, the data presented here suggest several exciting possibilities for the treatment of mood and anxiety disorders. First, a chronic intermittent dosing regimen lends itself to the potential prophylactic treatment of neuropsychiatric diseases. As acute doses of serotonergic psychedelics produce similar effects as an acute dose of the psychoplastogen ketamine, and ketamine has demonstrated promise for preventing stress-induced depression- and anxiety-related phenotypes in animal models, (64−66) it will be interesting to see if psychedelic microdosing is also capable of preventing the development of depression and anxiety symptoms. Second, the ability of low doses of DMT to produce positive effects on mood and anxiety in rats suggests that the perceptual effects of psychedelics can be decoupled from their therapeutic properties. This could lead to the development of nonhallucinogenic psychoplastogens with broad therapeutic potential and minimal risk for abuse. Taken together, our results encourage cautious optimism about the potential for psychedelic microdosing to produce beneficial effects on depression and anxiety.

Methods

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Drugs

Solid DMT·fumarate (2:1) was prepared as described previously (67) and stored in the dark at −20 °C prior to use. For each administration, a solution of DMT·fumarate (2:1) in 0.9% sterile saline was freshly prepared and passed through a 0.2 μm syringe filter. For all experiments, DMT·fumarate (2:1) was administered at 1 mg/kg (calculated based on the weight of the 2:1 DMT:fumarate salt) via intraperitoneal injection using an injection volume of 1 mL/kg. For our vehicle control, 0.9% sterile saline solution was utilized.

Animals

Male and female Sprague Dawley rats were obtained from Charles River Laboratories (Wilmington, MA), were housed two animals of the same sex per cage, and were given ad libitum access to food and water. The experiments began when the rats were 8 weeks of age. Lights in the vivarium were turned on at 07:00 h and turned off at 19:00 h. Behavioral experiments were performed during the light-on phase, with experiments taking place between 08:00 and 18:00 h unless otherwise noted. Treatment groups were randomly assigned, but each cage housed one animal from the DMT- and one from the VEH-treated groups. When appropriate, behavioral tests were counterbalanced to avoid systematic errors. All experimental procedures involving animals were approved by the UC Davis Institutional Animal Care and Use Committee (IACUC) and adhered to principles described in the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Over the course of one of the microdosing experiments, one animal began to exhibit signs of poor health, and was euthanized according to our IACUC protocol. The University of California, Davis is accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC). Details of behavioral tasks can be found in the Supplementary Methods.

Data Availability

Data that support the findings of this study are available from the corresponding author upon request.

Statistical Analysis

Data analyses were performed by experimenters blinded to treatment conditions. Statistical analyses were performed using GraphPad Prism (version 7.0a). Details of all statistical tests can be found in Supplementary Table 1. Appropriate samples sizes were estimated based on our previous experiences performing similar experiments in conjunction with a power analysis. The behavioral tests selected were based on specific hypotheses regarding the effects of psychedelic microdosing on mood, anxiety, cognitive function, and sociability. All comparisons presented were planned at the outset of the study.
As our study was designed to detect potential sex differences, each experiment was first analyzed using a one-way ANOVA with a Tukey’s post hoc test where each sex/treatment pair served as an independent group. When (1) comparisons between males and females within each treatment group (i.e., vehicle or DMT) were not significant, and (2) there was no difference between treatment groups of the same sex, the data from the two sexes were combined. However, in the case of the metabolism data presented in Figure S3, each sex/treatment pair was treated independently in an attempt to explain the sex differences in weight gain observed for the DMT-treated group.
In cases where several related phenotypes were measured (i.e., NIL and EPM), we performed a Z-normalization according to the method of Guilloux and co-workers (36) using vehicle-treated males as the control population. Then, we averaged the Z-scores for each animal across all of the measured phenotypes related to a particular behavioral experiment, to produce a single “behavioral score” (i.e., NIL Score or EPM Score). The Z-normalized values for each behavioral score were then compared using an unpaired Student’s t test.
In the case of fear conditioning and fear extinction experiments (Figure 3), a Mann–Whitney Test was used as a bimodal distribution was observed. Similar results in rat fear extinction experiments have been observed by others (68) and suggest that there are responders and nonresponders to extinction training. For the FST (Figure 4), video files were scored by two blinded observers and averaged. For gene expression studies (Figure 6) individual comparisons were made via two-tailed unpaired Student’s t tests, but the alpha for this family of experiments was adjusted using a Bonferroni correction. For the adiposity study, a two-way ANOVA with Sidak’s post hoc test was performed.
For the steroid profiling experiments, samples were split into male and female subgroups prior to statistical analysis. The Shapiro–Wilk normality test revealed normally distributed data in males and females. A heteroscedastic two-tailed Student’s t test and the Benjamini–Hochberg correction (69) was used to test for differences in steroid concentrations between treated and control animals. Student’s t test was performed in MS Excel, raw p-values were exported to R-studio where the “p.adjust” function was used to apply the Benjamini–Hochberg multiple comparisons adjustment accounting for all 18 steroid metabolites. For the steroid profiling studies, the ggplots2 package in R studio was used to create boxplots. Principal components analysis was performed using MetaboAnalyst 4.0.
For all statistical analyses, a Grubbs test was used to verify obvious outliers, and the specific data points omitted are listed in Supplementary Table 1. For the social interaction test, a computer error caused us to lose data for one animal.

Supporting Information

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acschemneuro.8b00692.

  • Results of NIL and EPM assays; SAB, NOR, and social approach paradigms; effects on weight and metabolism; effects on adiposity; quantification of serum steroid levels; supplementary methods (PDF)

  • Mass spectrometry-based metabolomics profiling (XLSX)

  • Statistical data (XLSX)

Terms & Conditions

Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

Author Information

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  • Corresponding Author
    • David E. Olson - Department of Chemistry, University of California, Davis, One Shields Avenue, Davis, California 95616, United States;  Department of Biochemistry & Molecular Medicine, School of Medicine, University of California, Davis, 2700 Stockton Blvd, Suite 2102, Sacramento, California 95817, United States;  Center for Neuroscience, University of California, Davis, 1544 Newton Ct, Davis, California 95618, United States;  Orcidhttp://orcid.org/0000-0002-4517-0543;  Email: [email protected]
  • Authors
    • Lindsay P. Cameron - Neuroscience Graduate Program, University of California, Davis, 1544 Newton Ct, Davis, California 95618, United States
    • Charlie J. Benson - Department of Chemistry, University of California, Davis, One Shields Avenue, Davis, California 95616, United States
    • Brian C. DeFelice - West Coast Metabolomics Center, University of California, Davis, One Shields Avenue, Davis, California 95616, United States
    • Oliver Fiehn - West Coast Metabolomics Center, University of California, Davis, One Shields Avenue, Davis, California 95616, United States;  Biochemistry Department, King Abdulaziz University, Jeddah, Saudi-Arabia;  Orcidhttp://orcid.org/0000-0002-6261-8928
  • Funding

    This work was supported by funds from the UC Davis Department of Chemistry and Department of Biochemistry & Molecular Medicine as well as a UC Davis Genome Center Pilot Grant (D.E.O.), NIH Grant 5T32MH082174-09 (L.P.C.), NIH Grant U24DK097154 (O.F.), NIH Grant R01DK104351 (B.C.D), and National Science Foundation Predoctoral Fellowship #1650042 (C.J.B.).

  • Notes
    D.E.O. is a co-founder of Delix Therapeutics, Inc.
    The authors declare no competing financial interest.

Acknowledgments

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We would like to thank Jennifer Rutkowsky and Jon Ramsey for performing the fat pad dissections, and the Intellectual and Developmental Disabilities Research Center (U54 HD079125) Rat Behavioral Testing Core for equipment use and assistance. We would also like to thank Lee Dunlap for synthesizing DMT, Zefan Hurley for help with the forced swim test, and Whitney Duim for assistance with imaging. The Olympus FV1000 confocal used in this study was purchased using NIH Shared Instrumentation Grant 1S10RR019266-01. We thank the MCB Light Microscopy Imaging Facility, which is a UC-Davis Campus Core Research Facility, for the use of this microscope.

References

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    Prochazkova Luisa; Lippelt Dominique P; Colzato Lorenza S; Sjoerds Zsuzsika; Hommel Bernhard; Colzato Lorenza S; Colzato Lorenza S; Kuchar Martin; Kuchar Martin
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    INTRODUCTION: Taking microdoses (a mere fraction of normal doses) of psychedelic substances, such as truffles, recently gained popularity, as it allegedly has multiple beneficial effects including creativity and problem-solving performance, potentially through targeting serotonergic 5-HT2A receptors and promoting cognitive flexibility, crucial to creative thinking. Nevertheless, enhancing effects of microdosing remain anecdotal, and in the absence of quantitative research on microdosing psychedelics, it is impossible to draw definitive conclusions on that matter. Here, our main aim was to quantitatively explore the cognitive-enhancing potential of microdosing psychedelics in healthy adults. METHODS: During a microdosing event organized by the Dutch Psychedelic Society, we examined the effects of psychedelic truffles (which were later analyzed to quantify active psychedelic alkaloids) on two creativity-related problem-solving tasks: the Picture Concept Task assessing convergent thinking and the Alternative Uses Task assessing divergent thinking. A short version of the Ravens Progressive Matrices task assessed potential changes in fluid intelligence. We tested once before taking a microdose and once while the effects were expected to be manifested. RESULTS: We found that both convergent and divergent thinking performance was improved after a non-blinded microdose, whereas fluid intelligence was unaffected. CONCLUSION: While this study provides quantitative support for the cognitive-enhancing properties of microdosing psychedelics, future research has to confirm these preliminary findings in more rigorous placebo-controlled study designs. Based on these preliminary results, we speculate that psychedelics might affect cognitive metacontrol policies by optimizing the balance between cognitive persistence and flexibility. We hope this study will motivate future microdosing studies with more controlled designs to test this hypothesis.
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  15. 15
    Yanakieva, S., Polychroni, N., Family, N., Williams, L. T. J., Luke, D. P., and Terhune, D. B. (2018) The effects of microdose LSD on time perception: a randomised, double-blind, placebo-controlled trial. Psychopharmacology 1– 12,  DOI: 10.1007/s00213-018-5119-x
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    Ly, C., Greb, A. C., Cameron, L. P., Wong, J. M., Barragan, E. V., Wilson, P. C., Burbach, K. F., Soltanzadeh Zarandi, S., Sood, A., Paddy, M. R., Duim, W. C., Dennis, M. Y., McAllister, A. K., Ori-McKenney, K. M., Gray, J. A., and Olson, D. E. (2018) Psychedelics Promote Structural and Functional Neural Plasticity. Cell Rep. 23, 3170– 3182,  DOI: 10.1016/j.celrep.2018.05.022
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    16
    Psychedelics Promote Structural and Functional Neural Plasticity
    Ly, Calvin; Greb, Alexandra C.; Cameron, Lindsay P.; Wong, Jonathan M.; Barragan, Eden V.; Wilson, Paige C.; Burbach, Kyle F.; Soltanzadeh Zarandi, Sina; Sood, Alexander; Paddy, Michael R.; Duim, Whitney C.; Dennis, Megan Y.; McAllister, A. Kimberley; Ori-McKenney, Kassandra M.; Gray, John A.; Olson, David E.
    Cell Reports (2018), 23 (11), 3170-3182CODEN: CREED8; ISSN:2211-1247. (Cell Press)
    Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiol. of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse no. and function, as measured by fluorescence microscopy and electrophysiol. The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clin. effectiveness of these compds. Our results underscore the therapeutic potential of psychedelics and, importantly, identify several lead scaffolds for medicinal chem. efforts focused on developing plasticity-promoting compds. as safe, effective, and fast-acting treatments for depression and related disorders.
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  17. 17
    Olson, D. E. (2018) ″Psychoplastogens: A Promising Class of Plasticity-Promoting Neurotherapeutics″. J. Exp. Neurosci. 12, 1– 4,  DOI: 10.1177/1179069518800508
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    Milad, M. R. and Quirk, G. J. (2002) Neurons in medial prefrontal cortex signal memory for fear extinction. Nature 420, 70– 74,  DOI: 10.1038/nature01138
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    18
    Neurons in medial prefrontal cortex signal memory for fear extinction
    Milad, Mohammed R.; Quirk, Gregory J.
    Nature (London, United Kingdom) (2002), 420 (6911), 70-74CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    Conditioned fear responses to a tone previously paired with a shock diminish if the tone is repeatedly presented without the shock, a process known as extinction. Since Pavlov it has been hypothesized that extinction does not erase conditioning, but forms a new memory. Destruction of the ventral medial prefrontal cortex, which consists of infralimbic and prelimbic cortices, blocks recall of fear extinction, indicating that medial prefrontal cortex might store long-term extinction memory. Here we show that infralimbic neurons recorded during fear conditioning and extinction fire to the tone only when rats are recalling extinction on the following day. Rats that froze the least showed the greatest increase in infralimbic tone responses. We also show that conditioned tones paired with brief elec. stimulation of infralimbic cortex elicit low freezing in rats that had not been extinguished. Thus, stimulation resembling extinction-induced infralimbic tone responses is able to simulate extinction memory. We suggest that consolidation of extinction learning potentiates infralimbic activity, which inhibits fear during subsequent encounters with fear stimuli.
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  19. 19
    Quirk, G. J., Likhtik, E., Pelletier, J. G., and Paré, D. (2003) Stimulation of medial prefrontal cortex decreases the responsiveness of central amygdala output neurons. J. Neurosci. 23, 8800– 8807,  DOI: 10.1523/JNEUROSCI.23-25-08800.2003
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    19
    Stimulation of medial prefrontal cortex decreases the responsiveness of central amygdala output neurons
    Quirk, Gregory J.; Likhtik, Ekaterina; Pelletier, Joe Guillaume; Pare, Denis
    Journal of Neuroscience (2003), 23 (25), 8800-8807CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)
    In extinction of auditory fear conditioning, rats learn that a tone no longer predicts the occurrence of a footshock. Recent lesion and unit recording studies suggest that the medial prefrontal cortex (mPFC) plays an essential role in the inhibition of conditioned fear following extinction. MPFC has robust projections to the amygdala, a structure that is known to mediate the acquisition and expression of conditioned fear. Fear conditioning potentiates the tone responses of neurons in the basolateral amygdala (BLA), which excite neurons in the central nucleus (Ce) of the amygdala. In turn, the Ce projects to the brainstem and hypothalamic areas that mediate fear responses. The present study was undertaken to test the hypothesis that the mPFC inhibits conditioned fear via feedforward inhibition of Ce output neurons. Recording extracellularly from physiol. identified brainstem-projecting Ce neurons, we tested the effect of mPFC prestimulation on Ce responsiveness to synaptic input. In support of our hypothesis, mPFC prestimulation dramatically reduced the responsiveness of Ce output neurons to inputs from the insular cortex and BLA. Thus, our findings support the idea that mPFC gates impulse transmission from the BLA to Ce, perhaps through GABAergic intercalated cells, thereby gating the expression of conditioned fear.
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  20. 20
    Hamani, C., Diwan, M., Macedo, C. E., Brandão, M. L., Shumake, J., Gonzalez-Lima, F., Raymond, R., Lozano, A. M., Fletcher, P. J., and Nobrega, J. N. (2010) Antidepressant-Like Effects of Medial Prefrontal Cortex Deep Brain Stimulation in Rats. Biol. Psychiatry 67, 117– 124,  DOI: 10.1016/j.biopsych.2009.08.025
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    20
    Antidepressant-like effects of medial prefrontal cortex deep brain stimulation in rats
    Hamani Clement; Diwan Mustansir; Macedo Carlos E; Brandao Marcus L; Shumake Jason; Gonzalez-Lima Francisco; Raymond Roger; Lozano Andres M; Fletcher Paul J; Nobrega Jose N
    Biological psychiatry (2010), 67 (2), 117-24 ISSN:.
    BACKGROUND: Subcallosal cingulate gyrus (SCG) deep brain stimulation (DBS) is being investigated as a treatment for major depression. We report on the effects of ventromedial prefrontal cortex (vmPFC) DBS in rats, focusing on possible mechanisms involved in an antidepressant-like response in the forced swim test (FST). METHODS: The outcome of vmPFC stimulation alone or combined with different types of lesions, including serotonin (5-HT) or norepineprhine (NE) depletion, was characterized in the FST. We also explored the effects of DBS on novelty-suppressed feeding, learned helplessness, and sucrose consumption in animals predisposed to helplessness. RESULTS: Stimulation at parameters approximating those used in clinical practice induced a significant antidepressant-like response in the FST. Ventromedial PFC lesions or local muscimol injections did not lead to a similar outcome. However, animals treated with vmPFC ibotenic acid lesions still responded to DBS, suggesting that the modulation of fiber near the electrodes could play a role in the antidepressant-like effects of stimulation. Also important was the integrity of the serotonergic system, as the effects of DBS in the FST were completely abolished in animals bearing 5-HT, but not NE, depleting lesions. In addition, vmPFC stimulation induced a sustained increase in hippocampal 5-HT levels. Preliminary work with other models showed that DBS was also able to influence specific aspects of depressive-like states in rodents, including anxiety and anhedonia, but not helplessness. CONCLUSIONS: Our study suggests that vmPFC DBS in rats may be useful to investigate mechanisms involved in the antidepressant effects of SCG DBS.
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  21. 21
    Warden, M. R., Selimbeyoglu, A., Mirzabekov, J. J., Lo, M., Thompson, K. R., Kim, S.-Y., Adhikari, A., Tye, K. M., Frank, L. M., and Deisseroth, K. (2012) A prefrontal cortex-brainstem neuronal projection that controls response to behavioural challenge. Nature 492, 428– 432,  DOI: 10.1038/nature11617
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    21
    A prefrontal cortex-brainstem neuronal projection that controls response to behavioural challenge
    Warden, Melissa R.; Selimbeyoglu, Aslihan; Mirzabekov, Julie J.; Lo, Maisie; Thompson, Kimberly R.; Kim, Sung-Yon; Adhikari, Avishek; Tye, Kay M.; Frank, Loren M.; Deisseroth, Karl
    Nature (London, United Kingdom) (2012), 492 (7429), 428-432CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    The prefrontal cortex (PFC) is thought to participate in high-level control of the generation of behaviors (including the decision to execute actions); indeed, imaging and lesion studies in human beings have revealed that PFC dysfunction can lead to either impulsive states with increased tendency to initiate action, or to amotivational states characterized by symptoms such as reduced activity, hopelessness and depressed mood. Considering the opposite valence of these two phenotypes as well as the broad complexity of other tasks attributed to PFC, we sought to elucidate the PFC circuitry that favors effortful behavioral responses to challenging situations. Here we develop and use a quant. method for the continuous assessment and control of active response to a behavioral challenge, synchronized with single-unit electrophysiol. and optogenetics in freely moving rats. In recording from the medial PFC (mPFC), we obsd. that many neurons were not simply movement-related in their spike-firing patterns but instead were selectively modulated from moment to moment, according to the animal's decision to act in a challenging situation. Surprisingly, we next found that direct activation of principal neurons in the mPFC had no detectable causal effect on this behavior. We tested whether this behavior could be causally mediated by only a subclass of mPFC cells defined by specific downstream wiring. Indeed, by leveraging optogenetic projection-targeting to control cells with specific efferent wiring patterns, we found that selective activation of those mPFC cells projecting to the brainstem dorsal raphe nucleus (DRN), a serotonergic nucleus implicated in major depressive disorder, induced a profound, rapid and reversible effect on selection of the active behavioral state. These results may be of importance in understanding the neural circuitry underlying normal and pathol. patterns of action selection and motivation in behavior.
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    Adhikari, A. (2015) Basomedial Amygdala Mediates Top-down Control of Anxiety and Fear. Nature 527, 179– 185,  DOI: 10.1038/nature15698
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    22
    Basomedial amygdala mediates top-down control of anxiety and fear
    Adhikari, Avishek; Lerner, Talia N.; Finkelstein, Joel; Pak, Sally; Jennings, Joshua H.; Davidson, Thomas J.; Ferenczi, Emily; Gunaydin, Lisa A.; Mirzabekov, Julie J.; Ye, Li; Kim, Sung-Yon; Lei, Anna; Deisseroth, Karl
    Nature (London, United Kingdom) (2015), 527 (7577), 179-185CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    Anxiety-related conditions are among the most difficult neuropsychiatric diseases to treat pharmacol., but respond to cognitive therapies. There has therefore been interest in identifying relevant top-down pathways from cognitive control regions in medial prefrontal cortex (mPFC). Identification of such pathways could contribute to our understanding of the cognitive regulation of affect, and provide pathways for intervention. Previous studies have suggested that dorsal and ventral mPFC subregions exert opposing effects on fear, as do subregions of other structures. However, precise causal targets for top-down connections among these diverse possibilities have not been established. Here we show that the basomedial amygdala (BMA) represents the major target of ventral mPFC in amygdala in mice. Moreover, BMA neurons differentiate safe and aversive environments, and BMA activation decreases fear-related freezing and high-anxiety states. Lastly, we show that the ventral mPFC-BMA projection implements top-down control of anxiety state and learned freezing, both at baseline and in stress-induced anxiety, defining a broadly relevant new top-down behavioral regulation pathway.
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  23. 23
    Fuchikami, M., Thomas, A., Liu, R., Wohleb, E. S., Land, B. B., DiLeone, R. J., Aghajanian, G. K., and Duman, R. S. (2015) Optogenetic stimulation of infralimbic PFC reproduces ketamine’s rapid and sustained antidepressant actions. Proc. Natl. Acad. Sci. U. S. A. 112, 8106– 8111,  DOI: 10.1073/pnas.1414728112
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    23
    Optogenetic stimulation of infralimbic PFC reproduces ketamine's rapid and sustained antidepressant actions
    Fuchikami, Manabu; Thomas, Alexandra; Liu, Rongjian; Wohleb, Eric S.; Land, Benjamin B.; Di Leone, Ralph J.; Aghajanian, George K.; Duman, Ronald S.
    Proceedings of the National Academy of Sciences of the United States of America (2015), 112 (26), 8106-8111CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    Ketamine produces rapid and sustained antidepressant actions in depressed patients, but the precise cellular mechanisms underlying these effects have not been identified. Here we detd. if modulation of neuronal activity in the infralimbic prefrontal cortex (IL-PFC) underlies the antidepressant and anxiolytic actions of ketamine. We found that neuronal inactivation of the IL-PFC completely blocked the antidepressant and anxiolytic effects of systemic ketamine in rodent models and that ketamine microinfusion into IL-PFC reproduced these behavioral actions of systemic ketamine. We also found that optogenetic stimulation of the IL-PFC produced rapid and long-lasting antidepressant and anxiolytic effects and that these effects are assocd. with increased no. and function of spine synapses of layer V pyramidal neurons. The results demonstrate that ketamine infusions or optogenetic stimulation of IL-PFC are sufficient to produce long-lasting antidepressant behavioral and synaptic responses similar to the effects of systemic ketamine administration.
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    Cameron, L. P., Benson, C. J., Dunlap, L. E., and Olson, D. E. (2018) Effects of N,N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression. ACS Chem. Neurosci. 9, 1582– 1590,  DOI: 10.1021/acschemneuro.8b00134
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    24
    Effects of N,N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression
    Cameron, Lindsay P.; Benson, Charlie J.; Dunlap, Lee E.; Olson, David E.
    ACS Chemical Neuroscience (2018), 9 (7), 1582-1590CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
    Depression and anxiety disorders are debilitating diseases resulting in substantial economic costs to society. Traditional antidepressants often take weeks to months to pos. affect mood and are ineffective for about 30% of the population. Alternatives, such as ketamine, a dissociative anesthetic capable of producing hallucinations, and the psychoactive tisane ayahuasca, have shown great promise due to their fast-acting nature and effectiveness in treatment-resistant populations. Here, we investigate the effects of N,N-dimethyltryptamine (DMT), the principle hallucinogenic component of ayahuasca, in rodent behavioral assays relevant to anxiety and depression using adult, male, Sprague-Dawley rats. We find that while DMT elicits initial anxiogenic responses in several of these paradigms, its long-lasting effects tend to reduce anxiety by facilitating the extinction of cued fear memory. Furthermore, DMT reduces immobility in the forced swim test, which is a characteristic behavioral response induced by many antidepressants. Our results demonstrate that DMT produces antidepressant and anxiolytic behavioral effects in rodents, warranting further investigation of ayahuasca and classical psychedelics as treatments for depression and post-traumatic stress disorder.
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  25. 25
    Carbonaro, T. M. and Gatch, M. B. (2016) Neuropharmacology of N,N-dimethyltryptamine. Brain Res. Bull. 126, 74– 88,  DOI: 10.1016/j.brainresbull.2016.04.016
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    25
    Neuropharmacology of N,N-dimethyltryptamine
    Carbonaro, Theresa M.; Gatch, Michael B.
    Brain Research Bulletin (2016), 126 (Part_1), 74-88CODEN: BRBUDU; ISSN:0361-9230. (Elsevier)
    N,N-dimethyltryptamine (DMT) is an indole alkaloid widely found in plants and animals. It is best known for producing brief and intense psychedelic effects when ingested. Increasing evidence suggests that endogenous DMT plays important roles for a no. of processes in the periphery and central nervous system, and may act as a neurotransmitter. This paper reviews the current literature of both the recreational use of DMT and its potential roles as an endogenous neurotransmitter. Pharmacokinetics, mechanisms of action in the periphery and central nervous system, clin. uses and adverse effects are also reviewed. DMT appears to have limited neurotoxicity and other adverse effects except for intense cardiovascular effects when administered i.v. in large doses. Because of its role in nervous system signaling, DMT may be a useful exptl. tool in exploring how the brain works, and may also be a useful clin. tool for treatment of anxiety and psychosis.
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    Davis, M. and Sheard, M. H. (1974) Biphasic dose-response effects of N-N-dimethyltryptamine on the rat startle reflex. Pharmacol. Biochem. Behav. 2, 827– 829,  DOI: 10.1016/0091-3057(74)90116-6
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    26
    Biphasic dose-response effects of N,N-dimethyltryptamine on the rat startle reflex
    Davis, Michael; Sheard, Michael H.
    Pharmacology, Biochemistry and Behavior (1974), 2 (6), 827-9CODEN: PBBHAU; ISSN:0091-3057.
    N,N-dimethyltryptamine (I) [61-50-7] (0.12 mg/kg, i.p.) increased the startle reflex in rats, but at 4.0 mg/kg it decreased the reflex. The startle reflex appears to be enhanced when midbrain raphe neurons are inhibited, but decreased when cells postsynaptic to raphe neurons are also inhibited.
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    Brewster, J. M., Siegel, R. K., Johnson, C. A., and Jarvik, M. E. (2017) Observational determination of dose-response curves in hallucinogen-treated monkeys. Int. Pharmacopsychiatry 11, 102– 108,  DOI: 10.1159/000468218
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    File, S. E. (1977) Effects of N,N-dimethyltryptamine on behavioural habituation in the rat. Pharmacol. Biochem. Behav. 6, 163– 168,  DOI: 10.1016/0091-3057(77)90067-3
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    28
    Effects of N,N-dimethyltryptamine on behavioral habituation in the rat
    File, Sandra E.
    Pharmacology, Biochemistry and Behavior (1977), 6 (2), 163-8CODEN: PBBHAU; ISSN:0091-3057.
    The processes involved in habituation and the various ways drugs might affect habituation are discussed. Exploration was measured in a holehoard and N,N-dimethyltryptamine (I) [61-50-7] (4 mg/kg) profoundly reduced the level of exploration, precluding any conclusions about the rate of habituation with this dose. However, both 2 and 4 mg I/kg prevented the 24-h retention of habituation of exploration. I (2 and 4 mg/kg) did not reduce the initial distraction to a tone stimulus, but the rate of habituation and its 24 h retention were imparied.
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    Stoff, D. M., Moja, E. A., Gillin, J. C., and Wyatt, R. J. (1978) Disruption of conditioned avoidance behavior by n,n-dimethyltryptamine (DMT) and stereotype by beta-phenylethylamine (PEA): animal models of attentional defects in schizophrenia. J. Psychiatr. Res. 14, 225– 240,  DOI: 10.1016/0022-3956(78)90025-0
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    29
    Disruption of conditioned avoidance behavior by N,N-dimethyltryptamine (DMT) and stereotype by β-phenylethylamine (PEA): animal models of attentional defects in schizophrenia
    Stoff, David M.; Moja, Egidio A.; Gillin, J. Christian; Wyatt, Richard Jed
    Journal of Psychiatric Research (1978), 14 (1-4), 225-40CODEN: JPYRA3; ISSN:0022-3956.
    Two drug-induced behaviors are described that satisfy some criteria as animal models for schizophrenia are described. One model is the disruption of shuttle box avoidance behavior in rats by N,N-dimethyltryptamine (I) [61-50-7], an effect which was dose-dependent and time-related. The rat did not become tolerant to repeated administration of I. The I effect was attenuated by acute administration of haloperidol [52-86-8] (0.05 mg/kg) but not by chlorpromazine [50-53-3] (0.5 mg/kg). Chronic chlorpromazine treatment did protect the rats from the disruptive effect of I. In rats pretreated with pargyline [555-57-7], a type B monoamine oxidase inhibitor, β-phenethylamine (PEA) [64-04-0] induced stereotyped behavior and increased locomotor activity in a dose-related manner. The neuroleptics tested were able to attenuate in a dose-related manner the stereotyped behavior induced by pargyline and PEA, whereas diazepam, which does not have antipsychotic activity, was inactive. The 2 models are particularly germane, because they deal with substances which are potential endogenous agents of schizophrenia. The use of animal models will increase the understanding of the biol. mechanisms of behavior, the mode of action of drugs, and perhaps even schizophrenia.
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  30. 30
    Walters, J. K., Sheard, M. H., and Davis, M. (1978) Effects of N,N-dimethyltryptamine (DMT) and 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) on shock elicited fighting in rats. Pharmacol. Biochem. Behav. 9, 87– 90,  DOI: 10.1016/0091-3057(78)90016-3
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    30
    Effects of N,N-dimethyltryptamine (DMT) and 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) on shock elicited fighting in rats
    Walters, James K.; Sheard, Michael H.; Davis, Michael
    Pharmacology, Biochemistry and Behavior (1978), 9 (1), 87-90CODEN: PBBHAU; ISSN:0091-3057.
    N,N-dimethyltryptamine (I) [61-50-7] (4-8.0 mg/kg, i.p.) and 5-methoxy-N,N-dimethyltryptamine (II) [1019-45-0] (0.5-2.0 mg/kg, i.p.) markedly depressed shock elicited fighting in rats, whereas at low doses there were no significant effects. Apparently, the action of the indole hallucinogens upon behavior is relatively specific and cannot be precisely defined from only a knowledge of their effects upon single units in the serotonergic system.
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    Sbordone, R. J., Wingard, J. A., Gorelick, D. A., and Elliott, M. L. (1979) Severe aggression in rats induced by mescaline but not other hallucinogens. Psychopharmacology (Berl) 66, 275– 280,  DOI: 10.1007/BF00428319
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    31
    Severe aggression in rats induced by mescaline but not other hallucinogens
    Sbordone, Robert J.; Wingard, Joseph A.; Gorelick, David A.; Elliott, Mark L.
    Psychopharmacology (Berlin, Germany) (1979), 66 (3), 275-80CODEN: PSCHDL; ISSN:0033-3158.
    Pairs of rats were administered mescaline-HCl (I-HCl) [832-92-8], lysergic acid diethylamide (LSD) [50-37-3], psilocin [520-53-6], N,N-dimethyltryptamine fumarate (DMT) [69321-46-6], 3,4-dimethoxyphenylethylamine-HCl (DMPEA) [635-85-8], or 5-hydroxydopamine (5-OHDA) [1927-04-4] i.p. prior to being placed in a shock-elicited aggression situation. When foot shock was delivered, controls struck each other with their forepaws, but never engaged in either biting or injurious fighting. I-treated rats (50 or 250 mg) rarely struck each other, but engaged in nearly lethal biting. Although LSD (25-400 μg/kg), psilocin (2.0 mg/kg), and DMT (5 mg/kg) produced some biting, this did not significantly differ from controls and never resulted in injuries. At higher doses, psilocin, DMT, and DMPEA decreased the amt. and intensity of fighting. Rats treated with 5-OHDA (8-200 mg/kg) or LSD (25-400 μg/kg) did not differ from controls. These results suggest that I's ability to induce pathol. aggression in rats exposed to foot shock is not shared by other hallucinogens or nonhallucinogenic I analogs.
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    Gatch, M. B., Rutledge, M. A., Carbonaro, T., and Forster, M. J. (2009) Comparison of the discriminative stimulus effects of dimethyltryptamine with different classes of psychoactive compounds in rats. Psychopharmacol. (Berl). 204, 715– 724,  DOI: 10.1007/s00213-009-1501-z
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    Comparison of the discriminative stimulus effects of dimethyltryptamine with different classes of psychoactive compounds in rats
    Gatch, Michael B.; Rutledge, Margaret A.; Carbonaro, Theresa; Forster, Michael J.
    Psychopharmacology (Berlin, Germany) (2009), 204 (4), 715-724CODEN: PSCHDL; ISSN:0033-3158. (Springer GmbH)
    Rationale: There has been increased recreational use of dimethyltryptamine (DMT), but little is known of its discriminative stimulus effects. Objectives: The present study assessed the similarity of the discriminative stimulus effects of DMT to other types of hallucinogens and to psychostimulants. Methods: Rats were trained to discriminate DMT from saline. To test the similarity of DMT to known hallucinogens, the ability of (+)-lysergic acid diethylamide (LSD), (-)-2,5-dimethoxy-4-methylamphetamine (DOM), (+)-methamphetamine, or (±)3,4-methylenedioxymethyl amphetamine (MDMA) to substitute in DMT-trained rats was tested. The ability of DMT to substitute in rats trained to discriminate each of these compds. was also tested. To assess the degree of similarity in discriminative stimulus effects, each of the compds. was tested for substitution in all of the other training groups. Results: LSD, DOM, and MDMA all fully substituted in DMT-trained rats, whereas DMT fully substituted only in DOM-trained rats. Full cross-substitution occurred between DMT and DOM, LSD and DOM, and (+)-methamphetamine and MDMA. MDMA fully substituted for (+)-methamphetamine, DOM, and DMT, but only partially for LSD. In MDMA-trained rats, LSD and (+)-methamphetamine fully substituted, whereas DMT and DOM did not fully substitute. No cross-substitution was evident between (+)-methamphetamine and DMT, LSD, or DOM. Conclusions: DMT produces discriminative stimulus effects most similar to those of DOM, with some similarity to the discriminative stimulus effects of LSD and MDMA. Like DOM and LSD, DMT seems to produce predominately hallucinogenic-like discriminative stimulus effects and minimal psychostimulant effects, in contrast to MDMA which produced hallucinogen- and psychostimulant-like effects.
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    Nair, A. B. and Jacob, S. (2016) A simple practice guide for dose conversion between animals and human. J. Basic Clin. Pharm. 7, 27– 31,  DOI: 10.4103/0976-0105.177703
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    A simple practice guide for dose conversion between animals and human
    Nair Anroop B; Jacob Shery
    Journal of basic and clinical pharmacy (2016), 7 (2), 27-31 ISSN:0976-0105.
    Understanding the concept of extrapolation of dose between species is important for pharmaceutical researchers when initiating new animal or human experiments. Interspecies allometric scaling for dose conversion from animal to human studies is one of the most controversial areas in clinical pharmacology. Allometric approach considers the differences in body surface area, which is associated with animal weight while extrapolating the doses of therapeutic agents among the species. This review provides basic information about translation of doses between species and estimation of starting dose for clinical trials using allometric scaling. The method of calculation of injection volume for parenteral formulation based on human equivalent dose is also briefed.
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    Strassman, R. J., Qualls, C. R., Uhlenhuth, E. H., and Kellner, R. (1994) Dose-response study of N,N-dimethyltryptamine in humans. II. Subjective effects and preliminary results of a new rating scale. Arch. Gen. Psychiatry 51, 98– 108,  DOI: 10.1001/archpsyc.1994.03950020022002
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    Dose-response study of N,N-dimethyltryptamine in humans. II. Subjective effects and preliminary results of a new rating scale
    Strassman, Rick J.; Qualls, Clifford R.; Uhlenhuth, Eberhard H.; Kellner, Robert
    Archives of General Psychiatry (1994), 51 (2), 98-108CODEN: ARGPAQ; ISSN:0003-990X.
    A review with 83 refs. The psychopharmacol. properties of different doses of N,N-dimethyltryptamine are studied using descriptions of effects clustered by a clin., mental status method. These effects are quantified using a newly developed rating scale, the Hallucinogen Rating Scale (HRS).
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    Turner, P., Brabb, T., Pekow, C., and Vasbinder, M. A. (2011) Administration of substances to laboratory animals: routes of administration and factors to consider. J. Am. Assoc. Lab Anim. Sci. 50, 600– 613
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    Administration of substances to laboratory animals: routes of administration and factors to consider
    Turner, Patricia V.; Brabb, Thea; Pekow, Cynthia; Vasbinder, Mary Ann
    Journal of the American Association for Laboratory Animal Science (2011), 50 (5), 600-613CODEN: JAALCY; ISSN:1559-6109. (American Association for Laboratory Animal Science)
    A review. Administration of substances to lab. animals requires careful consideration and planning to optimize delivery of the agent to the animal while minimizing potential adverse experiences from the procedure. For all species, many different routes are available for administration of substances. The research team and IACUC members should be aware of reasons for selecting specific routes and of training and competency necessary for personnel to use these routes effectively. Once a route is selected, issues such as vol. of administration, site of delivery, pH of the substance, and other factors must be considered to refine the technique. Inadequate training or inattention to detail during this aspect of a study may result in unintentional adverse effects on exptl. animals and confounded results.
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    Guilloux, J. P., Seney, M., Edgar, N., and Sibille, E. (2011) Integrated behavioral z-scoring increases the sensitivity and reliability of behavioral phenotyping in mice: relevance to emotionality and sex. J. Neurosci. Methods 197, 21– 31,  DOI: 10.1016/j.jneumeth.2011.01.019
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    Integrated behavioral z-scoring increases the sensitivity and reliability of behavioral phenotyping in mice: relevance to emotionality and sex
    Guilloux Jean-Philippe; Seney Marianne; Edgar Nicole; Sibille Etienne
    Journal of neuroscience methods (2011), 197 (1), 21-31 ISSN:.
    Defining anxiety- and depressive-like states in mice (emotionality) is best characterized by the use of complementary tests, leading sometimes to puzzling discrepancies and lack of correlation between similar paradigms. To address this issue, we hypothesized that integrating measures along the same behavioral dimensions in different tests would reduce the intrinsic variability of single tests and provide a robust characterization of the underlying "emotionality" of individual mouse, similarly as mood and related syndromes are defined in humans through various related symptoms over time. We describe the use of simple mathematical and integrative tools to help phenotype animals across related behavioral tests (syndrome diagnosis) and experiments (meta-analysis). We applied z-normalization across complementary measures of emotionality in different behavioral tests after unpredictable chronic mild stress (UCMS) or prolonged corticosterone exposure - two approaches to induce anxious-/depressive-like states in mice. Combining z-normalized test values, lowered the variance of emotionality measurement, enhanced the reliability of behavioral phenotyping, and increased analytical opportunities. Comparing integrated emotionality scores across studies revealed a robust sexual dimorphism in the vulnerability to develop high emotionality, manifested as higher UCMS-induced emotionality z-scores, but lower corticosterone-induced scores in females compared to males. Interestingly, the distribution of individual z-scores revealed a pattern of increased baseline emotionality in female mice, reminiscent of what is observed in humans. Together, we show that the z-scoring method yields robust measures of emotionality across complementary tests for individual mice and experimental groups, hence facilitating the comparison across studies and refining the translational applicability of these models.
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    Hughes, R. N. (2004) The value of spontaneous alternation behavior (SAB) as a test of retention in pharmacological investigations of memory. Neurosci. Biobehav. Rev. 28, 497– 505,  DOI: 10.1016/j.neubiorev.2004.06.006
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    The value of spontaneous alternation behavior (SAB) as a test of retention in pharmacological investigations of memory
    Hughes, Robert N.
    Neuroscience and Biobehavioral Reviews (2004), 28 (5), 497-505CODEN: NBREDE; ISSN:0149-7634. (Elsevier B.V.)
    A review. Because of its reliance on memory, the tendency for rats, mice and other animals to alternate successive choices of T- or Y-maze arms has assumed considerable popularity in pharmacol. studies of spatial memory as a quick and simple measure of retention that avoids the need for extensive training and the use of conventional reinforcers. Two forms of this tendency have been utilized, namely two-trial and continuous spontaneous alternation behavior (SAB). However, as the behavior can also reflect drug-related changes in sensory/attentional, motivational and performance processes, SAB should not be unquestionably accepted as a measure of memory alone. While assessments of post-acquisition drug effects on longer term memory may be possible through the appropriate timing of drug administration, this is more problematic if SAB is used as a measure of shorter term memory. Even though SAB can be a useful index of responsiveness to novelty, its value as a measure of retention is less certain. In this latter respect, a possible alternative to SAB testing might be the recently developed form of the related procedure, responsiveness to change.
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    Antunes, M. and Biala, G. (2012) The novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn. Process. 13, 93– 110,  DOI: 10.1007/s10339-011-0430-z
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    The novel object recognition memory: neurobiology, test procedure, and its modifications
    Antunes M; Biala G
    Cognitive processing (2012), 13 (2), 93-110 ISSN:.
    Animal models of memory have been considered as the subject of many scientific publications at least since the beginning of the twentieth century. In humans, memory is often accessed through spoken or written language, while in animals, cognitive functions must be accessed through different kind of behaviors in many specific, experimental models of memory and learning. Among them, the novel object recognition test can be evaluated by the differences in the exploration time of novel and familiar objects. Its application is not limited to a field of research and enables that various issues can be studied, such as the memory and learning, the preference for novelty, the influence of different brain regions in the process of recognition, and even the study of different drugs and their effects. This paper describes the novel object recognition paradigms in animals, as a valuable measure of cognition. The purpose of this work was to review the neurobiology and methodological modifications of the test commonly used in behavioral pharmacology.
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    Kaidanovich-Beilin, O., Lipina, T., Vukobradovic, I., Roder, J., and Woodgett, J. R. (2011) Assessment of Social Interaction Behaviors. J. Visualized Exp. 48, e2473  DOI: 10.3791/2473
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    Martin, D. A. and Nichols, C. D. (2017) The Effects of Hallucinogens on Gene Expression. Curr. Top. Behav. Neurosci. 36, 137– 158,  DOI: 10.1007/7854_2017_479
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    Vaidya, V. A., Marek, G. J., Aghajanian, G. K., and Duman, R. S. (1997) 5-HT2A receptor-mediated regulation of brain-derived neurotrophic factor mRNA in the hippocampus and the neocortex. J. Neurosci. 17, 2785– 2795,  DOI: 10.1523/JNEUROSCI.17-08-02785.1997
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    5-HT2A receptor-mediated regulation of brain-derived neurotrophic factor mRNA in the hippocampus and the neocortex
    Vaidya, Vidita A.; Marek, Gerard J.; Aghajanian, George K.; Duman, Ronald S.
    Journal of Neuroscience (1997), 17 (8), 2785-2795CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)
    The influence of 5-HT receptor agonists on the expression of BDNF in brain was detd. Administration of a hallucinogenic 5-HT2A/2C receptor agonist, but not a 5-HT1A receptor agonist, resulted in a significant but differential regulation of BDNF mRNA levels in hippocampus and neocortex. In the hippocampus, the 5-HT2A/2C receptor agonist significantly decreased BDNF mRNA expression in the dentate gyrus granule cell layer but did not influence expression of the neurotrophin in the CA subfields. In parietal cortex and other neocortical areas, but not piriform cortex, the 5-HT2A/2C receptor agonist dramatically increased the expression of BDNF mRNA. The effect of the 5-HT2A/2C receptor agonist on BDNF mRNA in both the hippocampus and the neocortex was blocked by pretreatment with a selective 5-HT2A, but not 5-HT2C, receptor antagonist. The expression of BDNF mRNA in the hippocampus is reported to be decreased by stress, raising the possibility that the 5-HT2A receptor mediates this effect. Pretreatment with ketanserin, a 5-HT2A/2C receptor antagonist, significantly blocked the stress-induced downregulation of BDNF mRNA in hippocampus, in support of this hypothesis. The results of this study raise the possibility that regulation of BDNF expression by hallucinogenic 5-HT2A receptor agonists leads to adaptations of synaptic strength in the hippocampus and the neocortex that may mediate some of the acute and long-term behavioral effects of these agents.
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    Martin, D. A., Marona-Lewicka, D., Nichols, D. E., and Nichols, C. D. (2014) Chronic LSD alters gene expression profiles in the mPFC relevant to schizophrenia. Neuropharmacology 83, 1– 8,  DOI: 10.1016/j.neuropharm.2014.03.013
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    Chronic LSD alters gene expression profiles in the mPFC relevant to schizophrenia
    Martin, David A.; Marona-Lewicka, Danuta; Nichols, David E.; Nichols, Charles D.
    Neuropharmacology (2014), 83 (), 1-8CODEN: NEPHBW; ISSN:0028-3908. (Elsevier B.V.)
    Chronic administration of lysergic acid diethylamide (LSD) every other day to rats results in a variety of abnormal behaviors. These build over the 90 day course of treatment and can persist at full strength for at least several months after cessation of treatment. The behaviors are consistent with those obsd. in animal models of schizophrenia and include hyperactivity, reduced sucrose-preference, and decreased social interaction. In order to elucidate mol. changes that underlie these aberrant behaviors, we chronically treated rats with LSD and performed RNA-sequencing on the medial prefrontal cortex (mPFC), an area highly assocd. with both the actions of LSD and the pathophysiol. of schizophrenia and other psychiatric illnesses. We obsd. widespread changes in the neurogenetic state of treated animals four weeks after cessation of LSD treatment. QPCR was used to validate a subset of gene expression changes obsd. with RNA-Seq, and confirmed a significant correlation between the two methods. Functional clustering anal. indicates differentially expressed genes are enriched in pathways involving neurotransmission (Drd2, Gabrb1), synaptic plasticity (Nr2a, Krox20), energy metab. (Atp5d, Ndufa1) and neuropeptide signaling (Npy, Bdnf), among others. Many processes identified as altered by chronic LSD are also implicated in the pathogenesis of schizophrenia, and genes affected by LSD are enriched with putative schizophrenia genes. Our results provide a relatively comprehensive anal. of mPFC transcriptional regulation in response to chronic LSD, and indicate that the long-term effects of LSD may bear relevance to psychiatric illnesses, including schizophrenia.
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    Griffiths, R. R., Richards, W. A., McCann, U., and Jesse, R. (2006) Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacol. (Berl) 187, 268– 294,  DOI: 10.1007/s00213-006-0457-5
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    Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance
    Griffiths, R. R.; Richards, W. A.; McCann, U.; Jesse, R.
    Psychopharmacology (Berlin, Germany) (2006), 187 (3), 268-283CODEN: PSCHDL; ISSN:0033-3158. (Springer GmbH)
    Rationale Although psilocybin has been used for centuries for religious purposes, little is known scientifically about its acute and persisting effects. Objectives This double-blind study evaluated the acute and longer-term psychol. effects of a high dose of psilocybin relative to a comparison compd. administered under comfortable, supportive conditions. Materials and methods The participants were hallucinogen-naive adults reporting regular participation in religious or spiritual activities. Two or three sessions were conducted at 2-mo intervals. Thirty volunteers received orally administered psilocybin (30 mg/70 kg) and methylphenidate hydrochloride (40 mg/70 kg) in counterbalanced order. To obscure the study design, six addnl. volunteers received methylphenidate in the first two sessions and unblinded psilocybin in a third session. The 8-h sessions were conducted individually. Volunteers were encouraged to close their eyes and direct their attention inward. Study monitors rated volunteers' behavior during sessions. Volunteers completed questionnaires assessing drug effects and mystical experience immediately after and 2 mo after sessions. Community observers rated changes in the volunteer's attitudes and behavior. Results Psilocybin produced a range of acute perceptual changes, subjective experiences, and labile moods including anxiety. Psilocybin also increased measures of mystical experience. At 2 mo, the volunteers rated the psilocybin experience as having substantial personal meaning and spiritual significance and attributed to the experience sustained pos. changes in attitudes and behavior consistent with changes rated by community observers. Conclusions When administered under supportive conditions, psilocybin occasioned experiences similar to spontaneously occurring mystical experiences. The ability to occasion such experiences prospectively will allow rigorous scientific investigations of their causes and consequences.
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    Griffiths, R. R., Johnson, M. W., Richards, W. A., Richards, B. D., McCann, U., and Jesse, R. (2011) Psilocybin occasioned mystical-type experiences: immediate and persisting dose-related effects. Psychopharmacology 218, 649– 665,  DOI: 10.1007/s00213-011-2358-5
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    Psilocybin occasioned mystical-type experiences: immediate and persisting dose-related effects
    Griffiths, Roland R.; Johnson, Matthew W.; Richards, William A.; Richards, Brian D.; McCann, Una; Jesse, Robert
    Psychopharmacology (Heidelberg, Germany) (2011), 218 (4), 649-665CODEN: PSCHDL; ISSN:0033-3158. (Springer)
    Rationale: This dose-effect study extends previous observations showing that psilocybin can occasion mystical-type experiences having persisting pos. effects on attitudes, mood, and behavior. Objectives: This double-blind study evaluated psilocybin (0, 5, 10, 20, 30 mg/70 kg, p.o.) administered under supportive conditions. Methods: Participants were 18 adults (17 hallucinogen-naive). Five 8-h sessions were conducted individually for each participant at 1-mo intervals. Participants were randomized to receive the four active doses in either ascending or descending order (nine participants each). Placebo was scheduled quasi-randomly. During sessions, volunteers used eyeshades and were instructed to direct their attention inward. Volunteers completed questionnaires assessing effects immediately after and 1 mo after each session, and at 14 mo follow-up. Results: Psilocybin produced acute perceptual and subjective effects including, at 20 and/or 30 mg/70 kg, extreme anxiety/fear (39% of volunteers) and/or mystical-type experience (72% of volunteers). One month after sessions at the two highest doses, volunteers rated the psilocybin experience as having substantial personal and spiritual significance, and attributed to the experience sustained pos. changes in attitudes, mood, and behavior, with the ascending dose sequence showing greater pos. effects. At 14 mo, ratings were undiminished and were consistent with changes rated by community observers. Both the acute and persisting effects of psilocybin were generally a monotonically increasing function of dose, with the lowest dose showing significant effects. Conclusions: Under supportive conditions, 20 and 30 mg/70 kg psilocybin occasioned mystical-type experiences having persisting pos. effects on attitudes, mood, and behavior. Implications for therapeutic trials are discussed.
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    Carhart-Harris, R. L. (2017) Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms. Sci. Rep. 7, 13817,  DOI: 10.1038/s41598-017-13282-7
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    Horsley, R. R., Pálenícek, T., Kolin, J., and Valeš, K. (2018) Psilocin and ketamine microdosing: effects of subchronic intermittent microdoses in the elevated plus-maze in male Wistar rats. Behav. Pharmacol. 29, 530– 536,  DOI: 10.1097/FBP.0000000000000394
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    Psilocin and ketamine microdosing: effects of subchronic intermittent microdoses in the elevated plus-maze in male Wistar rats
    Horsley, Rachel R.; Palenicek, Tomas; Kolin, Jan; Vales, Karel
    Behavioural Pharmacology (2018), 29 (6), 530-536CODEN: BPHAEL; ISSN:0955-8810. (Lippincott Williams & Wilkins)
    Short-term moderate doses of serotonergic and dissociative hallucinogens can be useful in the treatment of anxiety. Recently, a trend has developed for long-term intermittent 'microdosing' (usually one-tenth of a 'full' active dose), with reports of long-lasting relief from anxiety and related disorders; however, there is no scientific evidence for the efficacy of therapeutic microdosing nor to show its lasting effects. The objective of this study was to test for lasting effects on anxiety in rats after microdosing with ketamine or psilocin. Over 6 days, Wistar rats (N=40) were administered ketamine (0.5 or 3 mg/kg), psilocin (0.05 or 0.075 mg/kg), or saline on three occasions. A 5-min elevated plus-maze test was conducted 48 h after the final drug treatment (n=8). Dependent variables were entries (frequency), spent time (%), and distance traveled (cm) in each zone, as well as total frequency of rears, stretch-attend postures, and head dips. Statistical analyses of drug effects used sep. independent one-way anal. of variance and pair-wise comparisons using independent t-tests. Statistical effects were modest or borderline and were most consistent with a mildly anxiogenic profile, which was significant at lower doses; however, this conclusion remains tentative. The lower doses of ketamine and psilocin produced comparable effects (to one another) across each variable, as did the higher doses. This pattern of effects may suggest a common (e.g. neurotransmitter/receptor) mechanism. We conclude that microdosing with hallucinogens for therapeutic purposes might be counter-productive; however, more research is needed to confirm our findings and to establish their translational relevance to clin. 'psychedelic' therapy.
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    Young, M. B., Andero, R., Ressler, K. J., and Howell, L. L. (2015) 3,4-Methylenedioxymethamphetamine facilitates fear extinction learning. Transl. Psychiatry 5, e634  DOI: 10.1038/tp.2015.138
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    3,4-Methylenedioxymethamphetamine facilitates fear extinction learning
    Young, M. B.; Andero, R.; Ressler, K. J.; Howell, L. L.
    Translational Psychiatry (2015), 5 (9), e634CODEN: TPRSCF; ISSN:2158-3188. (Nature Publishing Group)
    Acutely administered 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') has been proposed to have long-term pos. effects on post-traumatic stress disorder (PTSD) symptoms when combined with psychotherapy. No preclin. data support a mechanistic basis for these claims. Given the persistent nature of psychotherapeutic gains facilitated by MDMA, we hypothesized that MDMA improves fear extinction learning, a key process in exposure-based therapies for PTSD. In these expts., mice were first exposed to cued fear conditioning and treated with drug vehicle or MDMA before extinction training 2 days later. MDMA was administered systemically and also directly targeted to brain structures known to contribute to extinction. In addn. to behavioral measures of extinction, changes in mRNA levels of brain-derived neurotrophic factor (Bdnf) and Fos were measured after MDMA treatment and extinction. MDMA (7.8 mg kg-1) persistently and robustly enhanced long-term extinction when administered before extinction training. MDMA increased the expression of Fos in the amygdala and medial prefrontal cortex (mPFC), whereas increases in Bdnf expression were obsd. only in the amygdala after extinction training. Extinction enhancements were recapitulated when MDMA (1 μg) was infused directly into the basolateral complex of the amygdala (BLA), and enhancement was abolished when BDNF signaling was inhibited before extinction. These findings suggest that MDMA enhances fear memory extinction through a BDNF-dependent mechanism, and that MDMA may be a useful adjunct to exposure-based therapies for PTSD and other anxiety disorders characterized by altered fear learning.
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    Dunlap, L. E., Andrews, A. M., and Olson, D. E. (2018) Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine. ACS Chem. Neurosci. 9, 2408– 2427,  DOI: 10.1021/acschemneuro.8b00155
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    Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine
    Dunlap, Lee E.; Andrews, Anne M.; Olson, David E.
    ACS Chemical Neuroscience (2018), 9 (10), 2408-2427CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
    Better known as "ecstasy", 3,4-methylenedioxymethamphetamine (MDMA) is a small mol. that has played a prominent role in defining the ethos of today's teenagers and young adults, much like lysergic acid diethylamide (LSD) did in the 1960s. Though MDMA possesses structural similarities to compds. like amphetamine and mescaline, it produces subjective effects that are unlike any of the classical psychostimulants or hallucinogens and is one of the few compds. capable of reliably producing prosocial behavioral states. As a result, MDMA has captured the attention of recreational users, the media, artists, psychiatrists, and neuropharmacologists alike. Here, we detail the synthesis of MDMA as well as its pharmacol., metab., adverse effects, and potential use in medicine. Finally, we discuss its history and why it is perhaps the most important compd. for the future of psychedelic science-having the potential to either facilitate new psychedelic research initiatives, or to usher in a second Dark Age for the field.
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    Sitaram, B. R., Lockett, L., Talomsin, R., Blackman, G. L., and McLeod, W. R. (1987) In vivo metabolism of 5-methoxy-N,N-dimethyltryptamine and N,N-dimethyltryptamine in the rat. Biochem. Pharmacol. 36, 1509– 1512,  DOI: 10.1016/0006-2952(87)90118-3
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    In vivo metabolism of 5-methoxy-N,N-dimethyltryptamine and N,N-dimethyltryptamine in the rat
    Sitaram, Balvant R.; Lockett, Lynn; Talomsin, Rerngjit; Blackman, Graeme L.; McLeod, William R.
    Biochemical Pharmacology (1987), 36 (9), 1509-12CODEN: BCPCA6; ISSN:0006-2952.
    Following i.p. administration, 5-methoxy-N,N-dimethyltryptamine and N,N-dimethyltryptamine are subject to both a very rapid uptake into, and clearance from, all tissues examd. The current studies in vivo confirm previous in vitro observations that the routes involved in the metab. of these compds. include oxidative deamination, N-demethylation, O-demethylation, and N-oxidn. The anal. of metabolic profiles in various tissues led to the identification of the N-oxides as major metabolites. The successful inhibition and redirection of metab. away from the indole acids towards the parent compds. and their structurally unique metabolites were demonstrated in animals pretreated with iproniazid.
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    Muschamp, J. W., Regina, M. J., Hull, E. M., Winter, J. C., and Rabin, R. A. (2004) Lysergic acid diethylamide and [-]-2,5-dimethoxy-4-methylamphetamine increase extracellular glutamate in rat prefrontal cortex. Brain Res. 1023, 134– 140,  DOI: 10.1016/j.brainres.2004.07.044
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    Lysergic acid diethylamide and [-]-2,5-dimethoxy-4-methylamphetamine increase extracellular glutamate in rat prefrontal cortex
    Muschamp, John W.; Regina, Meredith J.; Hull, Elaine M.; Winter, Jerrold C.; Rabin, Richard A.
    Brain Research (2004), 1023 (1), 134-140CODEN: BRREAP; ISSN:0006-8993. (Elsevier B.V.)
    The ability of hallucinogens to increase extracellular glutamate in the prefrontal cortex (PFC) was assessed by in vivo microdialysis. The hallucinogen lysergic acid diethylamide (LSD; 0.1 mg/kg, i.p.) caused a time-dependent increase in PFC glutamate that was blocked by the 5-HT2A antagonist M100907 (0.05 mg/kg, i.p.). Similarly, the 5-HT2A/C agonist [-]-2,5-dimethoxy-4-methylamphetamine (DOM; 0.6 mg/kg, i.p.), which is a phenethylamine hallucinogen, increased glutamate to 206% above saline-treated controls. When LSD (10 μM) was directly applied to the PFC by reverse dialysis, a rapid increase in PFC glutamate levels was obsd. Glutamate levels in the PFC remained elevated after the drug infusion was discontinued. These data provide direct evidence in vivo for the hypothesis that an enhanced release of glutamate is a common mechanism in the action of hallucinogens.
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    Bouso, J. C. (2015) Long-Term Use of Psychedelic Drugs Is Associated with Differences in Brain Structure and Personality in Humans. Eur. Neuropsychopharmacol. 25, 483– 492,  DOI: 10.1016/j.euroneuro.2015.01.008
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    Long-term use of psychedelic drugs is associated with differences in brain structure and personality in humans
    Bouso, Jose Carlos; Palhano-Fontes, Fernanda; Rodriguez-Fornells, Antoni; Ribeiro, Sidarta; Sanches, Rafael; Crippa, Jose Alexandre S.; Hallak, Jaime E. C.; de Araujo, Draulio B.; Riba, Jordi
    European Neuropsychopharmacology (2015), 25 (4), 483-492CODEN: EURNE8; ISSN:0924-977X. (Elsevier B.V.)
    Psychedelic agents have a long history of use by humans for their capacity to induce profound modifications in perception, emotion and cognitive processes. Despite increasing knowledge of the neural mechanisms involved in the acute effects of these drugs, the impact of sustained psychedelic use on the human brain remains largely unknown. Mol. pharmacol. studies have shown that psychedelic 5-hydroxytryptamine (5HT)2A agonists stimulate neurotrophic and transcription factors assocd. with synaptic plasticity. These data suggest that psychedelics could potentially induce structural changes in brain tissue. Here we looked for differences in cortical thickness (CT) in regular users of psychedelics. We obtained magnetic resonance imaging (MRI) images of the brains of 22 regular users of ayahuasca (a prepn. whose active principle is the psychedelic 5HT2A agonist N,N-dimethyltryptamine (DMT)) and 22 controls matched for age, sex, years of education, verbal IQ and fluid IQ. Ayahuasca users showed significant CT differences in midline structures of the brain, with thinning in the posterior cingulate cortex (PCC), a key node of the default mode network. CT values in the PCC were inversely correlated with the intensity and duration of prior use of ayahuasca and with scores on self-transcendence, a personality trait measuring religiousness, transpersonal feelings and spirituality. Although direct causation cannot be established, these data suggest that regular use of psychedelic drugs could potentially lead to structural changes in brain areas supporting attentional processes, self-referential thought, and internal mentation. These changes could underlie the previously reported personality changes in long-term users and highlight the involvement of the PCC in the effects of psychedelics.
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    Bouso, J. C. (2012) Personality, psychopathology, life attitudes and neuropsychological performance among ritual users of Ayahuasca: a longitudinal study. PLoS One 7, e42421  DOI: 10.1371/journal.pone.0042421
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    Personality, psychopathology, life attitudes and neuropsychological performance among ritual users of ayahuasca: a longitudinal study
    Bouso, Jose Carlos; Gonzalez, Debora; Fondevila, Sabela; Cutchet, Marta; Fernandez, Xavier; Barbosa, Paulo Cesar Ribeiro; Alcazar-Corcoles, Miguel Angel; Araujo, Wladimyr Sena; Barbanoj, Manel J.; Fabregas, Josep Maria; Riba, Jordi
    PLoS One (2012), 7 (8), e42421CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
    Ayahuasca is an Amazonian psychoactive plant beverage contg. the serotonergic 5-HT2A agonist N,N-dimethyltryptamine (DMT) and monoamine oxidase-inhibiting alkaloids (harmine, harmaline and tetrahydroharmine) that render it orally active. Ayahuasca ingestion is a central feature in several Brazilian syncretic churches that have expanded their activities to urban Brazil, Europe and North America. Members of these groups typically ingest ayahuasca at least twice per mo. Prior research has shown that acute ayahuasca increases blood flow in prefrontal and temporal brain regions and that it elicits intense modifications in thought processes, perception and emotion. However, regular ayahuasca use does not seem to induce the pattern of addiction-related problems that characterize drugs of abuse. To study the impact of repeated ayahuasca use on general psychol. well-being, mental health and cognition, here we assessed personality, psychopathol., life attitudes and neuropsychol. performance in regular ayahuasca users (n = 127) and controls (n = 115) at baseline and 1 yr later. Controls were actively participating in non-ayahuasca religions. Users showed higher Reward Dependence and Self-Transcendence and lower Harm Avoidance and Self-Directedness. They scored significantly lower on all psychopathol. measures, showed better performance on the Stroop test, the Wisconsin Card Sorting Test and the Letter-No. Sequencing task from the WAIS-III, and better scores on the Frontal Systems Behavior Scale. Anal. of life attitudes showed higher scores on the Spiritual Orientation Inventory, the Purpose in Life Test and the Psychosocial Well-Being test. Despite the lower no. of participants available at follow-up, overall differences with controls were maintained one year later. In conclusion, we found no evidence of psychol. maladjustment, mental health deterioration or cognitive impairment in the ayahuasca-using group.
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    Marona-Lewicka, D., Nichols, C. D., and Nichols, D. E. (2011) An Animal Model of Schizophrenia Based on Chronic LSD Administration: Old Idea, New Results. Neuropharmacology 61, 503– 512,  DOI: 10.1016/j.neuropharm.2011.02.006
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    An animal model of schizophrenia based on chronic LSD administration: Old idea, new results
    Marona-Lewicka, Danuta; Nichols, Charles D.; Nichols, David E.
    Neuropharmacology (2011), 61 (3), 503-512CODEN: NEPHBW; ISSN:0028-3908. (Elsevier B.V.)
    Many people who take LSD experience a second temporal phase of LSD intoxication that is qual. different, and was described by Daniel Freedman as "clearly a paranoid state. " We have previously shown that the discriminative stimulus effects of LSD in rats also occur in two temporal phases, with initial effects mediated by activation of 5-HT2A receptors (LSD30), and the later temporal phase mediated by dopamine D2-like receptors (LSD90). Surprisingly, we have now found that non-competitive NMDA antagonists produced full substitution in LSD90 rats, but only in older animals, whereas in LSD30, or in younger animals, these drugs did not mimic LSD. Chronic administration of low doses of LSD (>3 mo, 0.16 mg/kg every other day) induces a behavioral state characterized by hyperactivity and hyperirritability, increased locomotor activity, anhedonia, and impairment in social interaction that persists at the same magnitude for at least three months after cessation of LSD treatment. These behaviors, which closely resemble those assocd. with psychosis in humans, are not induced by withdrawal from LSD; rather, they are the result of neuroadaptive changes occurring in the brain during the chronic administration of LSD. These persistent behaviors are transiently reversed by haloperidol and olanzapine, but are insensitive to MDL-100907. Gene expression anal. data show that chronic LSD treatment produced significant changes in multiple neurotransmitter system-related genes, including those for serotonin and dopamine. Thus, we propose that chronic treatment of rats with low doses of LSD can serve as a new animal model of psychosis that may mimic the development and progression of schizophrenia, as well as model the established disease better than current acute drug administration models utilizing amphetamine or NMDA antagonists such as PCP.
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    Buchborn, T., Schröder, H., Höllt, V., and Grecksch, G. (2014) Repeated lysergic acid diethylamide in an animal model of depression: Normalisation of learning behaviour and hippocampal serotonin 5-HT2 signalling. J. Psychopharmacol. 28, 545– 552,  DOI: 10.1177/0269881114531666
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    Repeated lysergic acid diethylamide in an animal model of depression: normalisation of learning behaviour and hippocampal serotonin 5-HT2 signalling
    Buchborn, Tobias; Schroeder, Helmut; Hoellt, Volker; Grecksch, Gisela
    Journal of Psychopharmacology (London, United Kingdom) (2014), 28 (6), 545-552, 8 pp.CODEN: JOPSEQ; ISSN:0269-8811. (Sage Publications Ltd.)
    A re-balance of postsynaptic serotonin (5-HT) receptor signalling, with an increase in 5-HT1A and a decrease in 5-HT2A signalling, is a final common pathway multiple antidepressants share. Given that the 5-HT1A/2A agonist lysergic acid diethylamide (LSD), when repeatedly applied, selectively downregulates 5-HT2A, but not 5-HT1A receptors, one might expect LSD to similarly re-balance the postsynaptic 5-HT signalling. Challenging this idea, we use an animal model of depression specifically responding to repeated antidepressant treatment (olfactory bulbectomy), and test the antidepressant-like properties of repeated LSD treatment (0.13 mg/kg/d, 11 d). In line with former findings, we observe that bulbectomized rats show marked deficits in active avoidance learning. These deficits, similarly as we earlier noted with imipramine, are largely reversed by repeated LSD administration. Addnl., bulbectomized rats exhibit distinct anomalies of monoamine receptor signalling in hippocampus and/or frontal cortex; from these, only the hippocampal decrease in 5-HT2 related [35S]-GTP-gamma-S binding is normalized by LSD. Importantly, the sham-operated rats do not profit from LSD, and exhibit reduced hippocampal 5-HT2 signalling. As behavioral deficits after bulbectomy respond to agents classified as antidepressants only, we conclude that the effect of LSD in this model can be considered antidepressant-like, and discuss it in terms of a re-balance of hippocampal 5-HT2/5-HT1A signalling.
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    González-Maeso, J., Ebersole, B. J., Wurmbach, E., Lira, A., Zhou, M., Weisstaub, N., Hen, R., Gingrich, J. A., and Sealfon, S. C. (2003) Transcriptome Fingerprints Distinguish Hallucinogenic and Nonhallucinogenic 5-Hydroxytryptamine 2A Receptor Agonist Effects in Mouse Somatosensory Cortex. J. Neurosci. 23, 8836– 8843,  DOI: 10.1523/JNEUROSCI.23-26-08836.2003
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    Transcriptome fingerprints distinguish hallucinogenic and nonhallucinogenic 5-hydroxytryptamine 2A receptor agonist effects in mouse somatosensory cortex
    Gonzalez-Maeso, Javier; Yuen, Tony; Ebersole, Barbara J.; Wurmbach, Elisa; Lira, Alena; Zhou, Mingming; Weisstaub, Noelia; Hen, Rene; Gingrich, Jay A.; Sealfon, Stuart C.
    Journal of Neuroscience (2003), 23 (26), 8836-8843CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)
    Most neuropharmacol. agents and many drugs of abuse modulate the activity of heptahelical G-protein-coupled receptors. Although the effects of these ligands result from changes in cellular signaling, their neurobehavioral activity may not correlate with results of in vitro signal transduction assays. 5-Hydroxytryptamine 2A receptor (5-HT2AR) partial agonists that have similar pharmacol. profiles differ in the behavioral responses they elicit. In vitro studies suggest that different agonists acting at the same receptor may establish distinct patterns of signal transduction. Testing this hypothesis in the brain requires a global signal transduction assay that is applicable in vivo. To distinguish the cellular effects of the different 5-HT2AR agonists, we developed an assay for global signal transduction on the basis of high throughput quantification of rapidly modulated transcripts. Study of the responses to agonists in human embryonic kidney 293 cells stably expressing 5-HT2ARs demonstrated that each agonist elicits a distinct transcriptome fingerprint. We therefore studied behavioral and cortical signal transduction responses in wild-type and 5-HT2AR null-mutant mice. The hallucinogenic chems. (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) and lysergic acid diethylamide (LSD) stimulated a head-twitch behavioral response that was not obsd. with the nonhallucinogenic lisuride hydrogen maleate (LHM) and was absent in receptor null-mutant mice. We also found that DOI, LSD, and LHM each induced distinct transcriptome fingerprints in somatosensory cortex that were absent in 5-HT2AR null-mutants. Moreover, DOI and LSD showed similarities in the transcriptome fingerprints obtained that were not obsd. with the behaviorally inactive drug LHM. Our results demonstrate that chems. acting at the 5-HT2AR induced specific cellular response patterns in vivo that are reflected in unique changes in the somatosensory cortex transcriptome.
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    Vaidya, V. A., Marek, G. J., Aghajanian, G. K., and Duman, R. S. (1997) 5-HT2A receptor-mediated regulation of brain-derived neurotrophic factor mRNA in the hippocampus and the neocortex. J. Neurosci. 17, 2785– 2795,  DOI: 10.1523/JNEUROSCI.17-08-02785.1997
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    5-HT2A receptor-mediated regulation of brain-derived neurotrophic factor mRNA in the hippocampus and the neocortex
    Vaidya, Vidita A.; Marek, Gerard J.; Aghajanian, George K.; Duman, Ronald S.
    Journal of Neuroscience (1997), 17 (8), 2785-2795CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)
    The influence of 5-HT receptor agonists on the expression of BDNF in brain was detd. Administration of a hallucinogenic 5-HT2A/2C receptor agonist, but not a 5-HT1A receptor agonist, resulted in a significant but differential regulation of BDNF mRNA levels in hippocampus and neocortex. In the hippocampus, the 5-HT2A/2C receptor agonist significantly decreased BDNF mRNA expression in the dentate gyrus granule cell layer but did not influence expression of the neurotrophin in the CA subfields. In parietal cortex and other neocortical areas, but not piriform cortex, the 5-HT2A/2C receptor agonist dramatically increased the expression of BDNF mRNA. The effect of the 5-HT2A/2C receptor agonist on BDNF mRNA in both the hippocampus and the neocortex was blocked by pretreatment with a selective 5-HT2A, but not 5-HT2C, receptor antagonist. The expression of BDNF mRNA in the hippocampus is reported to be decreased by stress, raising the possibility that the 5-HT2A receptor mediates this effect. Pretreatment with ketanserin, a 5-HT2A/2C receptor antagonist, significantly blocked the stress-induced downregulation of BDNF mRNA in hippocampus, in support of this hypothesis. The results of this study raise the possibility that regulation of BDNF expression by hallucinogenic 5-HT2A receptor agonists leads to adaptations of synaptic strength in the hippocampus and the neocortex that may mediate some of the acute and long-term behavioral effects of these agents.
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    Smith, R. L., Canton, H., Barrett, R. J., and Sanders-Bush, E. (1998) Agonist properties of N,N-dimethyltryptamine at serotonin 5-HT2A and 5-HT2C receptors. Pharmacol., Biochem. Behav. 61, 323– 30,  DOI: 10.1016/S0091-3057(98)00110-5
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    Agonist properties of N,N-dimethyltryptamine at serotonin 5-HT2A and 5-HT2C receptors
    Smith, Randy L.; Canton, Herve; Barrett, Robert J.; Sanders-Bush, Elaine
    Pharmacology, Biochemistry and Behavior (1998), 61 (3), 323-330CODEN: PBBHAU; ISSN:0091-3057. (Elsevier Science Inc.)
    Extensive behavioral and biochem. evidence suggests an agonist role at the 5-HT2A receptor, and perhaps the 5-HT2C receptor, in the mechanism of action of hallucinogenic drugs. However the published in vitro pharmacol. properties of N,N-dimethyltryptamine (DMT), an hallucinogenic tryptamine analog, are not consistent with this hypothesis. We, therefore, undertook an extensive investigation into the properties of DMT at 5-HT2A and 5-HT2C receptors. In fibroblasts transfected with the 5-HT2A receptor or the 5-HT2C receptor, DMT activated the major intracellular signaling pathway (phosphoinositide hydrolysis) to an extent comparable to that produced by serotonin. Because drug efficacy changes with receptor d. and cellular micro-environment, we also examd. the properties of DMT in native prepns. using a behavioral and biochem. approach. Rats were trained to discriminate an antagonist ketanserin from an agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) in a two-lever choice paradigm. Pharmacol. studies showed that responding on the DOI and ketanserin lever reflected agonist and antagonist activity at 5-HT2A receptors, and hence, was a suitable model for evaluating the in vivo functional properties of DMT. Like other 5-HT2A receptor agonists, DMT substituted fully for DOI. Intact choroid plexus was used to evaluate the agonist properties at endogenous 5-HT2C receptors; DMT was a partial agonist at 5-HT2C receptors in this native prepn. Thus, we conclude that DMT behaves as an agonist at both 5-HT2A and 5-HT2A receptors. One difference was evident in that the 5-HT2C, but not the 5-HT2A, receptor showed a profound desensitization to DMT over time. This difference is interesting in light of the recent report that the hallucinogenic activity of DMT does not tolerate in humans and suggests the 5-HT2C receptor plays a less prominent role in the action of DMT.
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    Strassman, R. J., Qualls, C. R., and Berg, L. M. (1996) Differential tolerance to biological and subjective effects of four closely spaced doses of N,N-dimethyltryptamine in humans. Biol. Psychiatry 39, 784– 795,  DOI: 10.1016/0006-3223(95)00200-6
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    Differential tolerance to biological and subjective effects of four closely spaced doses of N,N-dimethyltryptamine in humans
    Strassman, Rick J.; Qualls, Clifford R.; Berg, Laura M.
    Biological Psychiatry (1996), 39 (9), 784-795CODEN: BIPCBF; ISSN:0006-3223. (Elsevier)
    Tolerance to the behavioral effects of the short-acting, endogenous hallucinogen, N,N-dimethyltryptamine (DMT) is seen inconsistently in animals, and has not been produced in humans. The nature and time course of responses to repetitive, closely spaced administrations of an hallucinogenic dose of DMT were characterized. Thirteen experienced hallucinogen users received i.v. 0.3 mg/kg DMT fumarate, or saline placebo, four times, at 30 min intervals, on 2 sep. days, in a randomized, double-blind, design. Tolerance to "psychedelic" subjective effects did not occur according to either clin. interview or Hallucinogen Rating Scale scores. Adrenocorticotropic hormone (ACTH), prolactin, cortisol, and heart rate responses decreased with repeated DMT administration, although blood pressure did not. These data demonstrate the unique properties of DMT relative to other hallucinogens and underscore the differential regulation of the multiple processes mediating the effects of DMT.
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    Duman, R. S. and Monteggia, L. M. (2006) A Neurotrophic Model for Stress-Related Mood Disorders. Biol. Psychiatry 59, 1116– 1127,  DOI: 10.1016/j.biopsych.2006.02.013
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    59
    A Neurotrophic Model for Stress-Related Mood Disorders
    Duman, Ronald S.; Monteggia, Lisa M.
    Biological Psychiatry (2006), 59 (12), 1116-1127CODEN: BIPCBF; ISSN:0006-3223. (Elsevier Inc.)
    A review. There is a growing body of evidence demonstrating that stress decreases the expression of brain-derived neurotrophic factor (BDNF) in limbic structures that control mood and that antidepressant treatment reverses or blocks the effects of stress. Decreased levels of BDNF, as well as other neruotrophic factors, could contribute to the atrophy of certain limbic structures, including the hippocampus and prefrontal cortex that has been obsd. in depressed subjects. Conversely, the neurotrophic actions of antidepressants could reverse neuronal atrophy and cell loss and thereby contribute to the therapeutic actions of these treatments. This review provides a crit. examn. of the neurotrophic hypothesis of depression that has evolved from this work, including anal. of preclin. cellular (adult neurogenesis) and behavioral models of depression and antidepressant actions, as well as clin. neuroimaging and postmortem studies. Although there are some limitations, the results of these studies are consistent with the hypothesis that decreased expression of BDNF and possibly other growth factors contributes to depression and that upregulation of BDNF plays a role in the actions of antidepressant treatment.
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    Santos, A. F. A., Vieira, A. L. S., Pic-Taylor, A., and Caldas, E. D. (2017) Reproductive effects of the psychoactive beverage ayahuasca in male Wistar rats after chronic exposure. Rev. Bras. Farmacogn. 27, 353– 360,  DOI: 10.1016/j.bjp.2017.01.006
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    60
    Reproductive effects of the psychoactive beverage ayahuasca in male Wistar rats after chronic exposure
    Santos, Alana de Fatima Andrade; Vieira, Ana Luiza Sarkis; Pic-Taylor, Aline; Caldas, Eloisa Dutra
    Revista Brasileira de Farmacognosia (2017), 27 (3), 353-360CODEN: RBFAEL; ISSN:0102-695X. (Elsevier Editora Ltda.)
    Ayahuasca is a psychoactive beverage used ancestrally by indigenous Amazonian tribes and, more recently, by Christian religions in Brazil and other countries. This study aimed to investigate the reproductive effects of this beverage in male Wistar rats after chronic exposure. The rats were treated by gavage every other day for 70 days at 0 (control), 1×, 2×, 4× and 8× the dose used in a religious ritual (12 animals per group), and animals euthanized on the 71st day. Compared to controls, there was a significant decrease in food consumption and body wt. gain in rats from the 4× and 8× groups, and a significant increase in the brain and stomach relative wt. at the 8× group. There was a significant increase in total serum testosterone, and a decrease in spermatic transit time and spermatic reserves in the epididymis caudae in the 4× group, but not in the highest dose group. No significant changes were found in the other reproductive endpoints (spermatozoid motility and morphol., total spermatozoid count and daily sperm prodn.), and histol. of testis and epididymis. This study identified a no-obsd.-adverse-effect-level for chronic and reproductive effects of ayahuasca in male Wistar rats at 2× the ritualistic dose, which corresponds in this study to 0.62 mg/kg bw N,N-dimethyltryptamine, 6.6 mg/kg bw harmine and 0.52 mg/kg bw harmaline. A potential toxic effect of ayahuasca in male rats was obsd. at the 4× dose, with a non-monotonic dose-response. Studies investigating the role of ayahuasca components in regulating testosterone levels are needed to better understand this action.
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    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsVGgs7s%253D&md5=248b18d42e590d3273615262059f9ea5
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  • Abstract

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    Figure 1

    Figure 1. Experimental design for testing the effects of chronic, intermittent, low doses of DMT on rats. Blue boxes indicate the days when drug was administered. Behavioral testing was performed on the days between doses. Gray boxes indicate days the animals spent in their home cages with no testing being performed. CLAMS = Comprehensive Lab Animal Monitoring System.

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    Figure 2

    Figure 2. Chronic, intermittent, low doses of DMT do not produce anxiogenic-like effects in rats. (a) DMT-treated and vehicle-treated groups display similar phenotypes in the NIL (a) and EPM (b) paradigms. Error bars represent SEM, ns = not significant. See Supplementary Table 1 for details of all statistical tests.

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    Figure 3. Chronic, intermittent, low doses of DMT enhance fear extinction in rats. (a) Experimental design for the fear conditioning and extinction experiments. (b, c) DMT- and vehicle-treated groups displayed comparable levels of freezing in the 2 min period before (b) and after (c) receiving foot shocks. (d, e) Neither contextual fear memory (d) nor cued fear memory (e) were impaired by chronic, intermittent treatment with low doses of DMT. (f) DMT-treated animals exhibited enhanced cued extinction memory as compared to vehicle-treated controls. n = 11 DMT-treated animals (5 male and 6 female), n = 12 vehicle-treated animals (6 male and 6 female); error bars represent SEM, ns = not significant, *p < 0.05. See Supplementary Table 1 for details of all statistical tests.

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    Figure 4

    Figure 4. Chronic, intermittent, low doses of DMT produce antidepressant-like effects in rats. Such effects include reduced immobility (a), increased climbing (b), and increased swimming (c) in the FST. Error bars represent SEM, ns = not significant, *p < 0.05. See Supplementary Table 1 for details of all statistical tests.

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    Figure 5

    Figure 5. Chronic, intermittent, low doses of DMT decrease dendritic spine density in the PFC of female, but not male, rats. (a) Dendritic spine density on layer V pyramidal neurons is reduced following psychedelic microdosing in females (DMT n = 20 cells from 2 animals; VEH n = 20 cells from 2 animals), but not males (DMT n = 12 cells from 2 animals; VEH n = 21 cells from 2 animals) as measured via Golgi–Cox staining. (b) Representative images of Golgi–Cox stained layer V pyramidal neurons in the PFC of rats. M = males, F = females, Error bars represent SEM, ns = not significant, *p < 0.05. See Supplementary Table 1 for details of all statistical tests.

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    Figure 6

    Figure 6. Chronic, intermittent, low doses of DMT produce minimal effects on gene expression in the PFC of rats. Gene expression studies (ddPCR) from rat PFC tissue indicate that psychedelic microdosing produces minimal effects on gene expression (n = 5 females and 3–5 males per group). To account for multiple hypothesis testing, a Bonferroni correction was made such that the α = 0.05/6 comparisons = 0.0083 for this family of experiments. Error bars represent SEM, ns = not significant. See Supplementary Table 1 for details of all statistical tests.

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      4-phosphorloxy-N,N-dimethyltryptamine (psilocybin) and methylenedioxymethamfetamine (MDMA), best known for their illegal use as psychedelic drugs, are showing promise as therapeutics in a resurgence of clinical research during the past 10 years. Psilocybin is being tested for alcoholism, smoking cessation, and in patients with advanced cancer with anxiety. MDMA is showing encouraging results as a treatment for refractory post-traumatic stress disorder, social anxiety in autistic adults, and anxiety associated with a life-threatening illness. Both drugs are studied as adjuncts or catalysts to psychotherapy, rather than as stand-alone drug treatments. This model of drug-assisted psychotherapy is a possible alternative to existing pharmacological and psychological treatments in psychiatry. Further research is needed to fully assess the potential of these compounds in the management of these common disorders that are difficult to treat with existing methods.
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    7. 7
      Carhart-Harris, R. L. and Goodwin, G. M. (2017) The therapeutic potential of psychedelic drugs: past, present, and future. Neuropsychopharmacology 42, 2105– 2113,  DOI: 10.1038/npp.2017.84
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      7
      The Therapeutic Potential of Psychedelic Drugs: Past, Present, and Future
      Carhart-Harris, Robin L.; Goodwin, Guy M.
      Neuropsychopharmacology (2017), 42 (11), 2105-2113CODEN: NEROEW; ISSN:0893-133X. (Nature Research)
      Plant-based psychedelics, such as psilocybin, have an ancient history of medicinal use. After the first English language report on LSD in 1950, psychedelics enjoyed a short-lived relationship with psychol. and psychiatry. Used most notably as aids to psychotherapy for the treatment of mood disorders and alc. dependence, drugs such as LSD showed initial therapeutic promise before prohibitive legislature in the mid-1960s effectively ended all major psychedelic research programs. Since the early 1990s, there has been a steady revival of human psychedelic research: last year saw reports on the first modern brain imaging study with LSD and three sep. clin. trials of psilocybin for depressive symptoms. In this circumspective piece, RLC-H and GMG share their opinions on the promises and pitfalls of renewed psychedelic research, with a focus on the development of psilocybin as a treatment for depression.
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    8. 8
      dos Santos, R. G., Osório, F. L., Crippa, J. A. S., Riba, J., Zuardi, A. W., and Hallak, J. E. C. (2016) Antidepressive, Anxiolytic, and Antiaddictive Effects of Ayahuasca, Psilocybin and Lysergic Acid Diethylamide (LSD): A Systematic Review of Clinical Trials Published in the Last 25 Years. Ther. Adv. Psychopharmacol. 6, 193– 213,  DOI: 10.1177/2045125316638008
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      8
      Antidepressive, anxiolytic, and antiaddictive effects of ayahuasca, psilocybin and lysergic acid diethylamide (LSD): a systematic review of clinical trials published in the last 25
      dos Santos, Rafael G.; Osorio, Flavia L.; Crippa, Alexandre S. Jose; Riba, Jordi; Zuardi, Antonio W.; Hallak, Jaime E. C.
      Therapeutic Advances in Psychopharmacology (2016), 6 (3), 193-213CODEN: TAPHB2; ISSN:2045-1261. (Sage Publications)
      To date, pharmacol. treatments for mood and anxiety disorders and for drug dependence show limited efficacy, leaving a large no. of patients suffering severe and persistent symptoms. Preliminary studies in animals and humans suggest that ayahuasca, psilocybin and lysergic acid diethylamide (LSD) may have antidepressive, anxiolytic, and antiaddictive properties. Thus, we conducted a systematic review of clin. trials published from 1990 until 2015, assessing these therapeutic properties. Electronic searches were performed using the PubMed, LILACS, and SciELO databases. Only clin. trials published in peer-reviewed journals were included. Of these, 151 studies were identified, of which six met the established criteria. Reviewed studies suggest beneficial effects for treatment-resistant depression, anxiety and depression assocd. with life-threatening diseases, and tobacco and alc. dependence. All drugs were well tolerated. In conclusion, ayahuasca, psilocybin and LSD may be useful pharmacol. tools for the treatment of drug dependence, and anxiety and mood disorders, esp. in treatment-resistant patients. These drugs may also be useful pharmacol. tools to understand psychiatric disorders and to develop new therapeutic agents. However, all studies reviewed had small sample sizes, and half of them were open-label, proof-of-concept studies. Randomized, double-blind, placebo-controlled studies with more patients are needed to replicate these preliminary findings.
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    9. 9
      Kyzar, E. J., Nichols, C. D., Gainetdinov, R. R., Nichols, D. E., and Kalueff, A. V. (2017) Psychedelic Drugs in Biomedicine. Trends Pharmacol. Sci. 38, 992– 1005,  DOI: 10.1016/j.tips.2017.08.003
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      Psychedelic Drugs in Biomedicine
      Kyzar, Evan J.; Nichols, Charles D.; Gainetdinov, Raul R.; Nichols, David E.; Kalueff, Allan V.
      Trends in Pharmacological Sciences (2017), 38 (11), 992-1005CODEN: TPHSDY; ISSN:0165-6147. (Elsevier Ltd.)
      A review. Psychedelic drugs, such as lysergic acid diethylamide (LSD), mescaline, and psilocybin, exert profound effects on brain and behavior. After decades of difficulties in studying these compds., psychedelics are again being tested as potential treatments for intractable biomedical disorders. Preclin. research of psychedelics complements human neuroimaging studies and pilot clin. trials, suggesting these compds. as promising treatments for addiction, depression, anxiety, and other conditions. However, many questions regarding the mechanisms of action, safety, and efficacy of psychedelics remain. Here, we summarize recent preclin. and clin. data in this field, discuss their pharmacol. mechanisms of action, and outline crit. areas for future studies of psychedelic drugs, with the goal of maximizing the potential benefits of translational psychedelic biomedicine to patients.
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    10. 10
      Cameron, L. P. and Olson, D. E. (2018) Dark Classics in Chemical Neuroscience: N,N-Dimethyltryptamine (DMT). ACS Chem. Neurosci. 9, 2344– 2357,  DOI: 10.1021/acschemneuro.8b00101
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      10
      Dark Classics in Chemical Neuroscience: N,N-Dimethyltryptamine (DMT)
      Cameron, Lindsay P.; Olson, David E.
      ACS Chemical Neuroscience (2018), 9 (10), 2344-2357CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
      A review. Though relatively obscure, N,N-dimethyltryptamine (DMT) is an important mol. in psychopharmacol. as it is the archetype for all indole-contg. serotonergic psychedelics. Its structure can be found embedded within those of better-known mols. such as lysergic acid diethylamide (LSD) and psilocybin. Unlike the latter two compds., DMT is ubiquitous, being produced by a wide variety of plant and animal species. It is one of the principal psychoactive components of ayahuasca, a tisane made from various plant sources that has been used for centuries. Furthermore, DMT is one of the few psychedelic compds. produced endogenously by mammals, and its biol. function in human physiol. remains a mystery. In this review, the authors cover the synthesis of DMT as well as its pharmacol., metab., adverse effects, and potential use in medicine. Finally, the authors discuss the history of DMT in chem. neuroscience and why this underappreciated mol. is so important to the field of psychedelic science.
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    11. 11
      Johnstad, P. G. (2018) Powerful Substances in Tiny Amounts: An Interview Study of Psychedelic Microdosing. Nord. Stud. Alcohol Drugs 35, 39– 51,  DOI: 10.1177/1455072517753339
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      Anderson, T., Petranker, R., Dinh-Williams, L.-A., Rosenbaum, D., Weissman, C., Hapke, E., Hui, K., and Farb, N. (2019) Microdosing Psychedelics: Personality, mental health, and creativity differences in microdosers. Psychopharmacology 1– 10,  DOI: 10.1007/s00213-018-5106-2
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      Polito, V. and Stevenson, R. J. (2019) A Systematic Study of Microdosing Psychedelics. PLoS One 14, e0211023,  DOI: 10.1371/journal.pone.0211023
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      A systematic study of microdosing psychedelics
      Polito, Vince; Stevenson, Richard J.
      PLoS One (2019), 14 (2), e0211023CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
      The phenomenon of 'microdosing', i.e., regular ingestion of very small quantities of psychedelic substances, has seen a rapid explosion of popularity in recent years. Individuals who microdose report minimal acute effects from these substances yet claim a range of long-term general health and wellbeing benefits. There have been no published empirical studies of microdosing and the current legal and bureaucratic climate makes direct empirical investigation of the effects of psychedelics difficult. In Study One we conducted a systematic, observational investigation of individuals who microdose. We tracked the experiences of 98 microdosing participants, who provided daily ratings of psychol. functioning over a six week period. 63 of these addnl. completed a battery of psychometric measures tapping mood, attention, wellbeing, mystical experiences, personality, creativity, and sense of agency, at baseline and at completion of the study. Analyses of daily ratings revealed a general increase in reported psychol. functioning across all measures on dosing days but limited evidence of residual effects on following days. Analyses of pre and post study measures revealed redns. in reported levels of depression and stress; lower levels of distractibility; increased absorption; and increased neuroticism. To better understand these findings, in Study Two we investigated pre-existing beliefs and expectations about the effects of microdosing in a sample of 263 na.ovrddot.ive and experienced microdosers, so as to gauge expectancy bias. All participants believed that microdosing would have large and wide-ranging benefits in contrast to the limited outcomes reported by actual microdosers. Notably, the effects believed most likely to change were unrelated to the obsd. pattern of reported outcomes. The current results suggest that dose controlled empirical research on the impacts of microdosing on mental health and attentional capabilities are needed.
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    14. 14
      Prochazkova, L., Lippelt, D. P., Colzato, L. S., Kuchar, M., Sjoerds, Z., and Hommel, B. (2018) Exploring the effect of microdosing psychedelics on creativity in an open-label natural setting. Psychopharmacology (Berl) 235, 3401– 3413,  DOI: 10.1007/s00213-018-5049-7
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      14
      Exploring the effect of microdosing psychedelics on creativity in an open-label natural setting
      Prochazkova Luisa; Lippelt Dominique P; Colzato Lorenza S; Sjoerds Zsuzsika; Hommel Bernhard; Colzato Lorenza S; Colzato Lorenza S; Kuchar Martin; Kuchar Martin
      Psychopharmacology (2018), 235 (12), 3401-3413 ISSN:.
      INTRODUCTION: Taking microdoses (a mere fraction of normal doses) of psychedelic substances, such as truffles, recently gained popularity, as it allegedly has multiple beneficial effects including creativity and problem-solving performance, potentially through targeting serotonergic 5-HT2A receptors and promoting cognitive flexibility, crucial to creative thinking. Nevertheless, enhancing effects of microdosing remain anecdotal, and in the absence of quantitative research on microdosing psychedelics, it is impossible to draw definitive conclusions on that matter. Here, our main aim was to quantitatively explore the cognitive-enhancing potential of microdosing psychedelics in healthy adults. METHODS: During a microdosing event organized by the Dutch Psychedelic Society, we examined the effects of psychedelic truffles (which were later analyzed to quantify active psychedelic alkaloids) on two creativity-related problem-solving tasks: the Picture Concept Task assessing convergent thinking and the Alternative Uses Task assessing divergent thinking. A short version of the Ravens Progressive Matrices task assessed potential changes in fluid intelligence. We tested once before taking a microdose and once while the effects were expected to be manifested. RESULTS: We found that both convergent and divergent thinking performance was improved after a non-blinded microdose, whereas fluid intelligence was unaffected. CONCLUSION: While this study provides quantitative support for the cognitive-enhancing properties of microdosing psychedelics, future research has to confirm these preliminary findings in more rigorous placebo-controlled study designs. Based on these preliminary results, we speculate that psychedelics might affect cognitive metacontrol policies by optimizing the balance between cognitive persistence and flexibility. We hope this study will motivate future microdosing studies with more controlled designs to test this hypothesis.
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    15. 15
      Yanakieva, S., Polychroni, N., Family, N., Williams, L. T. J., Luke, D. P., and Terhune, D. B. (2018) The effects of microdose LSD on time perception: a randomised, double-blind, placebo-controlled trial. Psychopharmacology 1– 12,  DOI: 10.1007/s00213-018-5119-x
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    16. 16
      Ly, C., Greb, A. C., Cameron, L. P., Wong, J. M., Barragan, E. V., Wilson, P. C., Burbach, K. F., Soltanzadeh Zarandi, S., Sood, A., Paddy, M. R., Duim, W. C., Dennis, M. Y., McAllister, A. K., Ori-McKenney, K. M., Gray, J. A., and Olson, D. E. (2018) Psychedelics Promote Structural and Functional Neural Plasticity. Cell Rep. 23, 3170– 3182,  DOI: 10.1016/j.celrep.2018.05.022
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      16
      Psychedelics Promote Structural and Functional Neural Plasticity
      Ly, Calvin; Greb, Alexandra C.; Cameron, Lindsay P.; Wong, Jonathan M.; Barragan, Eden V.; Wilson, Paige C.; Burbach, Kyle F.; Soltanzadeh Zarandi, Sina; Sood, Alexander; Paddy, Michael R.; Duim, Whitney C.; Dennis, Megan Y.; McAllister, A. Kimberley; Ori-McKenney, Kassandra M.; Gray, John A.; Olson, David E.
      Cell Reports (2018), 23 (11), 3170-3182CODEN: CREED8; ISSN:2211-1247. (Cell Press)
      Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiol. of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse no. and function, as measured by fluorescence microscopy and electrophysiol. The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clin. effectiveness of these compds. Our results underscore the therapeutic potential of psychedelics and, importantly, identify several lead scaffolds for medicinal chem. efforts focused on developing plasticity-promoting compds. as safe, effective, and fast-acting treatments for depression and related disorders.
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    17. 17
      Olson, D. E. (2018) ″Psychoplastogens: A Promising Class of Plasticity-Promoting Neurotherapeutics″. J. Exp. Neurosci. 12, 1– 4,  DOI: 10.1177/1179069518800508
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      Milad, M. R. and Quirk, G. J. (2002) Neurons in medial prefrontal cortex signal memory for fear extinction. Nature 420, 70– 74,  DOI: 10.1038/nature01138
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      18
      Neurons in medial prefrontal cortex signal memory for fear extinction
      Milad, Mohammed R.; Quirk, Gregory J.
      Nature (London, United Kingdom) (2002), 420 (6911), 70-74CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      Conditioned fear responses to a tone previously paired with a shock diminish if the tone is repeatedly presented without the shock, a process known as extinction. Since Pavlov it has been hypothesized that extinction does not erase conditioning, but forms a new memory. Destruction of the ventral medial prefrontal cortex, which consists of infralimbic and prelimbic cortices, blocks recall of fear extinction, indicating that medial prefrontal cortex might store long-term extinction memory. Here we show that infralimbic neurons recorded during fear conditioning and extinction fire to the tone only when rats are recalling extinction on the following day. Rats that froze the least showed the greatest increase in infralimbic tone responses. We also show that conditioned tones paired with brief elec. stimulation of infralimbic cortex elicit low freezing in rats that had not been extinguished. Thus, stimulation resembling extinction-induced infralimbic tone responses is able to simulate extinction memory. We suggest that consolidation of extinction learning potentiates infralimbic activity, which inhibits fear during subsequent encounters with fear stimuli.
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    19. 19
      Quirk, G. J., Likhtik, E., Pelletier, J. G., and Paré, D. (2003) Stimulation of medial prefrontal cortex decreases the responsiveness of central amygdala output neurons. J. Neurosci. 23, 8800– 8807,  DOI: 10.1523/JNEUROSCI.23-25-08800.2003
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      19
      Stimulation of medial prefrontal cortex decreases the responsiveness of central amygdala output neurons
      Quirk, Gregory J.; Likhtik, Ekaterina; Pelletier, Joe Guillaume; Pare, Denis
      Journal of Neuroscience (2003), 23 (25), 8800-8807CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)
      In extinction of auditory fear conditioning, rats learn that a tone no longer predicts the occurrence of a footshock. Recent lesion and unit recording studies suggest that the medial prefrontal cortex (mPFC) plays an essential role in the inhibition of conditioned fear following extinction. MPFC has robust projections to the amygdala, a structure that is known to mediate the acquisition and expression of conditioned fear. Fear conditioning potentiates the tone responses of neurons in the basolateral amygdala (BLA), which excite neurons in the central nucleus (Ce) of the amygdala. In turn, the Ce projects to the brainstem and hypothalamic areas that mediate fear responses. The present study was undertaken to test the hypothesis that the mPFC inhibits conditioned fear via feedforward inhibition of Ce output neurons. Recording extracellularly from physiol. identified brainstem-projecting Ce neurons, we tested the effect of mPFC prestimulation on Ce responsiveness to synaptic input. In support of our hypothesis, mPFC prestimulation dramatically reduced the responsiveness of Ce output neurons to inputs from the insular cortex and BLA. Thus, our findings support the idea that mPFC gates impulse transmission from the BLA to Ce, perhaps through GABAergic intercalated cells, thereby gating the expression of conditioned fear.
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    20. 20
      Hamani, C., Diwan, M., Macedo, C. E., Brandão, M. L., Shumake, J., Gonzalez-Lima, F., Raymond, R., Lozano, A. M., Fletcher, P. J., and Nobrega, J. N. (2010) Antidepressant-Like Effects of Medial Prefrontal Cortex Deep Brain Stimulation in Rats. Biol. Psychiatry 67, 117– 124,  DOI: 10.1016/j.biopsych.2009.08.025
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      20
      Antidepressant-like effects of medial prefrontal cortex deep brain stimulation in rats
      Hamani Clement; Diwan Mustansir; Macedo Carlos E; Brandao Marcus L; Shumake Jason; Gonzalez-Lima Francisco; Raymond Roger; Lozano Andres M; Fletcher Paul J; Nobrega Jose N
      Biological psychiatry (2010), 67 (2), 117-24 ISSN:.
      BACKGROUND: Subcallosal cingulate gyrus (SCG) deep brain stimulation (DBS) is being investigated as a treatment for major depression. We report on the effects of ventromedial prefrontal cortex (vmPFC) DBS in rats, focusing on possible mechanisms involved in an antidepressant-like response in the forced swim test (FST). METHODS: The outcome of vmPFC stimulation alone or combined with different types of lesions, including serotonin (5-HT) or norepineprhine (NE) depletion, was characterized in the FST. We also explored the effects of DBS on novelty-suppressed feeding, learned helplessness, and sucrose consumption in animals predisposed to helplessness. RESULTS: Stimulation at parameters approximating those used in clinical practice induced a significant antidepressant-like response in the FST. Ventromedial PFC lesions or local muscimol injections did not lead to a similar outcome. However, animals treated with vmPFC ibotenic acid lesions still responded to DBS, suggesting that the modulation of fiber near the electrodes could play a role in the antidepressant-like effects of stimulation. Also important was the integrity of the serotonergic system, as the effects of DBS in the FST were completely abolished in animals bearing 5-HT, but not NE, depleting lesions. In addition, vmPFC stimulation induced a sustained increase in hippocampal 5-HT levels. Preliminary work with other models showed that DBS was also able to influence specific aspects of depressive-like states in rodents, including anxiety and anhedonia, but not helplessness. CONCLUSIONS: Our study suggests that vmPFC DBS in rats may be useful to investigate mechanisms involved in the antidepressant effects of SCG DBS.
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    21. 21
      Warden, M. R., Selimbeyoglu, A., Mirzabekov, J. J., Lo, M., Thompson, K. R., Kim, S.-Y., Adhikari, A., Tye, K. M., Frank, L. M., and Deisseroth, K. (2012) A prefrontal cortex-brainstem neuronal projection that controls response to behavioural challenge. Nature 492, 428– 432,  DOI: 10.1038/nature11617
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      21
      A prefrontal cortex-brainstem neuronal projection that controls response to behavioural challenge
      Warden, Melissa R.; Selimbeyoglu, Aslihan; Mirzabekov, Julie J.; Lo, Maisie; Thompson, Kimberly R.; Kim, Sung-Yon; Adhikari, Avishek; Tye, Kay M.; Frank, Loren M.; Deisseroth, Karl
      Nature (London, United Kingdom) (2012), 492 (7429), 428-432CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      The prefrontal cortex (PFC) is thought to participate in high-level control of the generation of behaviors (including the decision to execute actions); indeed, imaging and lesion studies in human beings have revealed that PFC dysfunction can lead to either impulsive states with increased tendency to initiate action, or to amotivational states characterized by symptoms such as reduced activity, hopelessness and depressed mood. Considering the opposite valence of these two phenotypes as well as the broad complexity of other tasks attributed to PFC, we sought to elucidate the PFC circuitry that favors effortful behavioral responses to challenging situations. Here we develop and use a quant. method for the continuous assessment and control of active response to a behavioral challenge, synchronized with single-unit electrophysiol. and optogenetics in freely moving rats. In recording from the medial PFC (mPFC), we obsd. that many neurons were not simply movement-related in their spike-firing patterns but instead were selectively modulated from moment to moment, according to the animal's decision to act in a challenging situation. Surprisingly, we next found that direct activation of principal neurons in the mPFC had no detectable causal effect on this behavior. We tested whether this behavior could be causally mediated by only a subclass of mPFC cells defined by specific downstream wiring. Indeed, by leveraging optogenetic projection-targeting to control cells with specific efferent wiring patterns, we found that selective activation of those mPFC cells projecting to the brainstem dorsal raphe nucleus (DRN), a serotonergic nucleus implicated in major depressive disorder, induced a profound, rapid and reversible effect on selection of the active behavioral state. These results may be of importance in understanding the neural circuitry underlying normal and pathol. patterns of action selection and motivation in behavior.
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    22. 22
      Adhikari, A. (2015) Basomedial Amygdala Mediates Top-down Control of Anxiety and Fear. Nature 527, 179– 185,  DOI: 10.1038/nature15698
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      22
      Basomedial amygdala mediates top-down control of anxiety and fear
      Adhikari, Avishek; Lerner, Talia N.; Finkelstein, Joel; Pak, Sally; Jennings, Joshua H.; Davidson, Thomas J.; Ferenczi, Emily; Gunaydin, Lisa A.; Mirzabekov, Julie J.; Ye, Li; Kim, Sung-Yon; Lei, Anna; Deisseroth, Karl
      Nature (London, United Kingdom) (2015), 527 (7577), 179-185CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      Anxiety-related conditions are among the most difficult neuropsychiatric diseases to treat pharmacol., but respond to cognitive therapies. There has therefore been interest in identifying relevant top-down pathways from cognitive control regions in medial prefrontal cortex (mPFC). Identification of such pathways could contribute to our understanding of the cognitive regulation of affect, and provide pathways for intervention. Previous studies have suggested that dorsal and ventral mPFC subregions exert opposing effects on fear, as do subregions of other structures. However, precise causal targets for top-down connections among these diverse possibilities have not been established. Here we show that the basomedial amygdala (BMA) represents the major target of ventral mPFC in amygdala in mice. Moreover, BMA neurons differentiate safe and aversive environments, and BMA activation decreases fear-related freezing and high-anxiety states. Lastly, we show that the ventral mPFC-BMA projection implements top-down control of anxiety state and learned freezing, both at baseline and in stress-induced anxiety, defining a broadly relevant new top-down behavioral regulation pathway.
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    23. 23
      Fuchikami, M., Thomas, A., Liu, R., Wohleb, E. S., Land, B. B., DiLeone, R. J., Aghajanian, G. K., and Duman, R. S. (2015) Optogenetic stimulation of infralimbic PFC reproduces ketamine’s rapid and sustained antidepressant actions. Proc. Natl. Acad. Sci. U. S. A. 112, 8106– 8111,  DOI: 10.1073/pnas.1414728112
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      23
      Optogenetic stimulation of infralimbic PFC reproduces ketamine's rapid and sustained antidepressant actions
      Fuchikami, Manabu; Thomas, Alexandra; Liu, Rongjian; Wohleb, Eric S.; Land, Benjamin B.; Di Leone, Ralph J.; Aghajanian, George K.; Duman, Ronald S.
      Proceedings of the National Academy of Sciences of the United States of America (2015), 112 (26), 8106-8111CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Ketamine produces rapid and sustained antidepressant actions in depressed patients, but the precise cellular mechanisms underlying these effects have not been identified. Here we detd. if modulation of neuronal activity in the infralimbic prefrontal cortex (IL-PFC) underlies the antidepressant and anxiolytic actions of ketamine. We found that neuronal inactivation of the IL-PFC completely blocked the antidepressant and anxiolytic effects of systemic ketamine in rodent models and that ketamine microinfusion into IL-PFC reproduced these behavioral actions of systemic ketamine. We also found that optogenetic stimulation of the IL-PFC produced rapid and long-lasting antidepressant and anxiolytic effects and that these effects are assocd. with increased no. and function of spine synapses of layer V pyramidal neurons. The results demonstrate that ketamine infusions or optogenetic stimulation of IL-PFC are sufficient to produce long-lasting antidepressant behavioral and synaptic responses similar to the effects of systemic ketamine administration.
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    24. 24
      Cameron, L. P., Benson, C. J., Dunlap, L. E., and Olson, D. E. (2018) Effects of N,N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression. ACS Chem. Neurosci. 9, 1582– 1590,  DOI: 10.1021/acschemneuro.8b00134
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      24
      Effects of N,N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression
      Cameron, Lindsay P.; Benson, Charlie J.; Dunlap, Lee E.; Olson, David E.
      ACS Chemical Neuroscience (2018), 9 (7), 1582-1590CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
      Depression and anxiety disorders are debilitating diseases resulting in substantial economic costs to society. Traditional antidepressants often take weeks to months to pos. affect mood and are ineffective for about 30% of the population. Alternatives, such as ketamine, a dissociative anesthetic capable of producing hallucinations, and the psychoactive tisane ayahuasca, have shown great promise due to their fast-acting nature and effectiveness in treatment-resistant populations. Here, we investigate the effects of N,N-dimethyltryptamine (DMT), the principle hallucinogenic component of ayahuasca, in rodent behavioral assays relevant to anxiety and depression using adult, male, Sprague-Dawley rats. We find that while DMT elicits initial anxiogenic responses in several of these paradigms, its long-lasting effects tend to reduce anxiety by facilitating the extinction of cued fear memory. Furthermore, DMT reduces immobility in the forced swim test, which is a characteristic behavioral response induced by many antidepressants. Our results demonstrate that DMT produces antidepressant and anxiolytic behavioral effects in rodents, warranting further investigation of ayahuasca and classical psychedelics as treatments for depression and post-traumatic stress disorder.
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    25. 25
      Carbonaro, T. M. and Gatch, M. B. (2016) Neuropharmacology of N,N-dimethyltryptamine. Brain Res. Bull. 126, 74– 88,  DOI: 10.1016/j.brainresbull.2016.04.016
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      25
      Neuropharmacology of N,N-dimethyltryptamine
      Carbonaro, Theresa M.; Gatch, Michael B.
      Brain Research Bulletin (2016), 126 (Part_1), 74-88CODEN: BRBUDU; ISSN:0361-9230. (Elsevier)
      N,N-dimethyltryptamine (DMT) is an indole alkaloid widely found in plants and animals. It is best known for producing brief and intense psychedelic effects when ingested. Increasing evidence suggests that endogenous DMT plays important roles for a no. of processes in the periphery and central nervous system, and may act as a neurotransmitter. This paper reviews the current literature of both the recreational use of DMT and its potential roles as an endogenous neurotransmitter. Pharmacokinetics, mechanisms of action in the periphery and central nervous system, clin. uses and adverse effects are also reviewed. DMT appears to have limited neurotoxicity and other adverse effects except for intense cardiovascular effects when administered i.v. in large doses. Because of its role in nervous system signaling, DMT may be a useful exptl. tool in exploring how the brain works, and may also be a useful clin. tool for treatment of anxiety and psychosis.
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    26. 26
      Davis, M. and Sheard, M. H. (1974) Biphasic dose-response effects of N-N-dimethyltryptamine on the rat startle reflex. Pharmacol. Biochem. Behav. 2, 827– 829,  DOI: 10.1016/0091-3057(74)90116-6
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      26
      Biphasic dose-response effects of N,N-dimethyltryptamine on the rat startle reflex
      Davis, Michael; Sheard, Michael H.
      Pharmacology, Biochemistry and Behavior (1974), 2 (6), 827-9CODEN: PBBHAU; ISSN:0091-3057.
      N,N-dimethyltryptamine (I) [61-50-7] (0.12 mg/kg, i.p.) increased the startle reflex in rats, but at 4.0 mg/kg it decreased the reflex. The startle reflex appears to be enhanced when midbrain raphe neurons are inhibited, but decreased when cells postsynaptic to raphe neurons are also inhibited.
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    27. 27
      Brewster, J. M., Siegel, R. K., Johnson, C. A., and Jarvik, M. E. (2017) Observational determination of dose-response curves in hallucinogen-treated monkeys. Int. Pharmacopsychiatry 11, 102– 108,  DOI: 10.1159/000468218
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      File, S. E. (1977) Effects of N,N-dimethyltryptamine on behavioural habituation in the rat. Pharmacol. Biochem. Behav. 6, 163– 168,  DOI: 10.1016/0091-3057(77)90067-3
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      28
      Effects of N,N-dimethyltryptamine on behavioral habituation in the rat
      File, Sandra E.
      Pharmacology, Biochemistry and Behavior (1977), 6 (2), 163-8CODEN: PBBHAU; ISSN:0091-3057.
      The processes involved in habituation and the various ways drugs might affect habituation are discussed. Exploration was measured in a holehoard and N,N-dimethyltryptamine (I) [61-50-7] (4 mg/kg) profoundly reduced the level of exploration, precluding any conclusions about the rate of habituation with this dose. However, both 2 and 4 mg I/kg prevented the 24-h retention of habituation of exploration. I (2 and 4 mg/kg) did not reduce the initial distraction to a tone stimulus, but the rate of habituation and its 24 h retention were imparied.
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    29. 29
      Stoff, D. M., Moja, E. A., Gillin, J. C., and Wyatt, R. J. (1978) Disruption of conditioned avoidance behavior by n,n-dimethyltryptamine (DMT) and stereotype by beta-phenylethylamine (PEA): animal models of attentional defects in schizophrenia. J. Psychiatr. Res. 14, 225– 240,  DOI: 10.1016/0022-3956(78)90025-0
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      29
      Disruption of conditioned avoidance behavior by N,N-dimethyltryptamine (DMT) and stereotype by β-phenylethylamine (PEA): animal models of attentional defects in schizophrenia
      Stoff, David M.; Moja, Egidio A.; Gillin, J. Christian; Wyatt, Richard Jed
      Journal of Psychiatric Research (1978), 14 (1-4), 225-40CODEN: JPYRA3; ISSN:0022-3956.
      Two drug-induced behaviors are described that satisfy some criteria as animal models for schizophrenia are described. One model is the disruption of shuttle box avoidance behavior in rats by N,N-dimethyltryptamine (I) [61-50-7], an effect which was dose-dependent and time-related. The rat did not become tolerant to repeated administration of I. The I effect was attenuated by acute administration of haloperidol [52-86-8] (0.05 mg/kg) but not by chlorpromazine [50-53-3] (0.5 mg/kg). Chronic chlorpromazine treatment did protect the rats from the disruptive effect of I. In rats pretreated with pargyline [555-57-7], a type B monoamine oxidase inhibitor, β-phenethylamine (PEA) [64-04-0] induced stereotyped behavior and increased locomotor activity in a dose-related manner. The neuroleptics tested were able to attenuate in a dose-related manner the stereotyped behavior induced by pargyline and PEA, whereas diazepam, which does not have antipsychotic activity, was inactive. The 2 models are particularly germane, because they deal with substances which are potential endogenous agents of schizophrenia. The use of animal models will increase the understanding of the biol. mechanisms of behavior, the mode of action of drugs, and perhaps even schizophrenia.
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    30. 30
      Walters, J. K., Sheard, M. H., and Davis, M. (1978) Effects of N,N-dimethyltryptamine (DMT) and 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) on shock elicited fighting in rats. Pharmacol. Biochem. Behav. 9, 87– 90,  DOI: 10.1016/0091-3057(78)90016-3
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      30
      Effects of N,N-dimethyltryptamine (DMT) and 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) on shock elicited fighting in rats
      Walters, James K.; Sheard, Michael H.; Davis, Michael
      Pharmacology, Biochemistry and Behavior (1978), 9 (1), 87-90CODEN: PBBHAU; ISSN:0091-3057.
      N,N-dimethyltryptamine (I) [61-50-7] (4-8.0 mg/kg, i.p.) and 5-methoxy-N,N-dimethyltryptamine (II) [1019-45-0] (0.5-2.0 mg/kg, i.p.) markedly depressed shock elicited fighting in rats, whereas at low doses there were no significant effects. Apparently, the action of the indole hallucinogens upon behavior is relatively specific and cannot be precisely defined from only a knowledge of their effects upon single units in the serotonergic system.
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    31. 31
      Sbordone, R. J., Wingard, J. A., Gorelick, D. A., and Elliott, M. L. (1979) Severe aggression in rats induced by mescaline but not other hallucinogens. Psychopharmacology (Berl) 66, 275– 280,  DOI: 10.1007/BF00428319
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      31
      Severe aggression in rats induced by mescaline but not other hallucinogens
      Sbordone, Robert J.; Wingard, Joseph A.; Gorelick, David A.; Elliott, Mark L.
      Psychopharmacology (Berlin, Germany) (1979), 66 (3), 275-80CODEN: PSCHDL; ISSN:0033-3158.
      Pairs of rats were administered mescaline-HCl (I-HCl) [832-92-8], lysergic acid diethylamide (LSD) [50-37-3], psilocin [520-53-6], N,N-dimethyltryptamine fumarate (DMT) [69321-46-6], 3,4-dimethoxyphenylethylamine-HCl (DMPEA) [635-85-8], or 5-hydroxydopamine (5-OHDA) [1927-04-4] i.p. prior to being placed in a shock-elicited aggression situation. When foot shock was delivered, controls struck each other with their forepaws, but never engaged in either biting or injurious fighting. I-treated rats (50 or 250 mg) rarely struck each other, but engaged in nearly lethal biting. Although LSD (25-400 μg/kg), psilocin (2.0 mg/kg), and DMT (5 mg/kg) produced some biting, this did not significantly differ from controls and never resulted in injuries. At higher doses, psilocin, DMT, and DMPEA decreased the amt. and intensity of fighting. Rats treated with 5-OHDA (8-200 mg/kg) or LSD (25-400 μg/kg) did not differ from controls. These results suggest that I's ability to induce pathol. aggression in rats exposed to foot shock is not shared by other hallucinogens or nonhallucinogenic I analogs.
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      Gatch, M. B., Rutledge, M. A., Carbonaro, T., and Forster, M. J. (2009) Comparison of the discriminative stimulus effects of dimethyltryptamine with different classes of psychoactive compounds in rats. Psychopharmacol. (Berl). 204, 715– 724,  DOI: 10.1007/s00213-009-1501-z
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      Comparison of the discriminative stimulus effects of dimethyltryptamine with different classes of psychoactive compounds in rats
      Gatch, Michael B.; Rutledge, Margaret A.; Carbonaro, Theresa; Forster, Michael J.
      Psychopharmacology (Berlin, Germany) (2009), 204 (4), 715-724CODEN: PSCHDL; ISSN:0033-3158. (Springer GmbH)
      Rationale: There has been increased recreational use of dimethyltryptamine (DMT), but little is known of its discriminative stimulus effects. Objectives: The present study assessed the similarity of the discriminative stimulus effects of DMT to other types of hallucinogens and to psychostimulants. Methods: Rats were trained to discriminate DMT from saline. To test the similarity of DMT to known hallucinogens, the ability of (+)-lysergic acid diethylamide (LSD), (-)-2,5-dimethoxy-4-methylamphetamine (DOM), (+)-methamphetamine, or (±)3,4-methylenedioxymethyl amphetamine (MDMA) to substitute in DMT-trained rats was tested. The ability of DMT to substitute in rats trained to discriminate each of these compds. was also tested. To assess the degree of similarity in discriminative stimulus effects, each of the compds. was tested for substitution in all of the other training groups. Results: LSD, DOM, and MDMA all fully substituted in DMT-trained rats, whereas DMT fully substituted only in DOM-trained rats. Full cross-substitution occurred between DMT and DOM, LSD and DOM, and (+)-methamphetamine and MDMA. MDMA fully substituted for (+)-methamphetamine, DOM, and DMT, but only partially for LSD. In MDMA-trained rats, LSD and (+)-methamphetamine fully substituted, whereas DMT and DOM did not fully substitute. No cross-substitution was evident between (+)-methamphetamine and DMT, LSD, or DOM. Conclusions: DMT produces discriminative stimulus effects most similar to those of DOM, with some similarity to the discriminative stimulus effects of LSD and MDMA. Like DOM and LSD, DMT seems to produce predominately hallucinogenic-like discriminative stimulus effects and minimal psychostimulant effects, in contrast to MDMA which produced hallucinogen- and psychostimulant-like effects.
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      Nair, A. B. and Jacob, S. (2016) A simple practice guide for dose conversion between animals and human. J. Basic Clin. Pharm. 7, 27– 31,  DOI: 10.4103/0976-0105.177703
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      A simple practice guide for dose conversion between animals and human
      Nair Anroop B; Jacob Shery
      Journal of basic and clinical pharmacy (2016), 7 (2), 27-31 ISSN:0976-0105.
      Understanding the concept of extrapolation of dose between species is important for pharmaceutical researchers when initiating new animal or human experiments. Interspecies allometric scaling for dose conversion from animal to human studies is one of the most controversial areas in clinical pharmacology. Allometric approach considers the differences in body surface area, which is associated with animal weight while extrapolating the doses of therapeutic agents among the species. This review provides basic information about translation of doses between species and estimation of starting dose for clinical trials using allometric scaling. The method of calculation of injection volume for parenteral formulation based on human equivalent dose is also briefed.
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      Strassman, R. J., Qualls, C. R., Uhlenhuth, E. H., and Kellner, R. (1994) Dose-response study of N,N-dimethyltryptamine in humans. II. Subjective effects and preliminary results of a new rating scale. Arch. Gen. Psychiatry 51, 98– 108,  DOI: 10.1001/archpsyc.1994.03950020022002
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      Dose-response study of N,N-dimethyltryptamine in humans. II. Subjective effects and preliminary results of a new rating scale
      Strassman, Rick J.; Qualls, Clifford R.; Uhlenhuth, Eberhard H.; Kellner, Robert
      Archives of General Psychiatry (1994), 51 (2), 98-108CODEN: ARGPAQ; ISSN:0003-990X.
      A review with 83 refs. The psychopharmacol. properties of different doses of N,N-dimethyltryptamine are studied using descriptions of effects clustered by a clin., mental status method. These effects are quantified using a newly developed rating scale, the Hallucinogen Rating Scale (HRS).
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      Turner, P., Brabb, T., Pekow, C., and Vasbinder, M. A. (2011) Administration of substances to laboratory animals: routes of administration and factors to consider. J. Am. Assoc. Lab Anim. Sci. 50, 600– 613
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      Administration of substances to laboratory animals: routes of administration and factors to consider
      Turner, Patricia V.; Brabb, Thea; Pekow, Cynthia; Vasbinder, Mary Ann
      Journal of the American Association for Laboratory Animal Science (2011), 50 (5), 600-613CODEN: JAALCY; ISSN:1559-6109. (American Association for Laboratory Animal Science)
      A review. Administration of substances to lab. animals requires careful consideration and planning to optimize delivery of the agent to the animal while minimizing potential adverse experiences from the procedure. For all species, many different routes are available for administration of substances. The research team and IACUC members should be aware of reasons for selecting specific routes and of training and competency necessary for personnel to use these routes effectively. Once a route is selected, issues such as vol. of administration, site of delivery, pH of the substance, and other factors must be considered to refine the technique. Inadequate training or inattention to detail during this aspect of a study may result in unintentional adverse effects on exptl. animals and confounded results.
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      Guilloux, J. P., Seney, M., Edgar, N., and Sibille, E. (2011) Integrated behavioral z-scoring increases the sensitivity and reliability of behavioral phenotyping in mice: relevance to emotionality and sex. J. Neurosci. Methods 197, 21– 31,  DOI: 10.1016/j.jneumeth.2011.01.019
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      Integrated behavioral z-scoring increases the sensitivity and reliability of behavioral phenotyping in mice: relevance to emotionality and sex
      Guilloux Jean-Philippe; Seney Marianne; Edgar Nicole; Sibille Etienne
      Journal of neuroscience methods (2011), 197 (1), 21-31 ISSN:.
      Defining anxiety- and depressive-like states in mice (emotionality) is best characterized by the use of complementary tests, leading sometimes to puzzling discrepancies and lack of correlation between similar paradigms. To address this issue, we hypothesized that integrating measures along the same behavioral dimensions in different tests would reduce the intrinsic variability of single tests and provide a robust characterization of the underlying "emotionality" of individual mouse, similarly as mood and related syndromes are defined in humans through various related symptoms over time. We describe the use of simple mathematical and integrative tools to help phenotype animals across related behavioral tests (syndrome diagnosis) and experiments (meta-analysis). We applied z-normalization across complementary measures of emotionality in different behavioral tests after unpredictable chronic mild stress (UCMS) or prolonged corticosterone exposure - two approaches to induce anxious-/depressive-like states in mice. Combining z-normalized test values, lowered the variance of emotionality measurement, enhanced the reliability of behavioral phenotyping, and increased analytical opportunities. Comparing integrated emotionality scores across studies revealed a robust sexual dimorphism in the vulnerability to develop high emotionality, manifested as higher UCMS-induced emotionality z-scores, but lower corticosterone-induced scores in females compared to males. Interestingly, the distribution of individual z-scores revealed a pattern of increased baseline emotionality in female mice, reminiscent of what is observed in humans. Together, we show that the z-scoring method yields robust measures of emotionality across complementary tests for individual mice and experimental groups, hence facilitating the comparison across studies and refining the translational applicability of these models.
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      Hughes, R. N. (2004) The value of spontaneous alternation behavior (SAB) as a test of retention in pharmacological investigations of memory. Neurosci. Biobehav. Rev. 28, 497– 505,  DOI: 10.1016/j.neubiorev.2004.06.006
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      The value of spontaneous alternation behavior (SAB) as a test of retention in pharmacological investigations of memory
      Hughes, Robert N.
      Neuroscience and Biobehavioral Reviews (2004), 28 (5), 497-505CODEN: NBREDE; ISSN:0149-7634. (Elsevier B.V.)
      A review. Because of its reliance on memory, the tendency for rats, mice and other animals to alternate successive choices of T- or Y-maze arms has assumed considerable popularity in pharmacol. studies of spatial memory as a quick and simple measure of retention that avoids the need for extensive training and the use of conventional reinforcers. Two forms of this tendency have been utilized, namely two-trial and continuous spontaneous alternation behavior (SAB). However, as the behavior can also reflect drug-related changes in sensory/attentional, motivational and performance processes, SAB should not be unquestionably accepted as a measure of memory alone. While assessments of post-acquisition drug effects on longer term memory may be possible through the appropriate timing of drug administration, this is more problematic if SAB is used as a measure of shorter term memory. Even though SAB can be a useful index of responsiveness to novelty, its value as a measure of retention is less certain. In this latter respect, a possible alternative to SAB testing might be the recently developed form of the related procedure, responsiveness to change.
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      Antunes, M. and Biala, G. (2012) The novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn. Process. 13, 93– 110,  DOI: 10.1007/s10339-011-0430-z
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      The novel object recognition memory: neurobiology, test procedure, and its modifications
      Antunes M; Biala G
      Cognitive processing (2012), 13 (2), 93-110 ISSN:.
      Animal models of memory have been considered as the subject of many scientific publications at least since the beginning of the twentieth century. In humans, memory is often accessed through spoken or written language, while in animals, cognitive functions must be accessed through different kind of behaviors in many specific, experimental models of memory and learning. Among them, the novel object recognition test can be evaluated by the differences in the exploration time of novel and familiar objects. Its application is not limited to a field of research and enables that various issues can be studied, such as the memory and learning, the preference for novelty, the influence of different brain regions in the process of recognition, and even the study of different drugs and their effects. This paper describes the novel object recognition paradigms in animals, as a valuable measure of cognition. The purpose of this work was to review the neurobiology and methodological modifications of the test commonly used in behavioral pharmacology.
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      Kaidanovich-Beilin, O., Lipina, T., Vukobradovic, I., Roder, J., and Woodgett, J. R. (2011) Assessment of Social Interaction Behaviors. J. Visualized Exp. 48, e2473  DOI: 10.3791/2473
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      Martin, D. A. and Nichols, C. D. (2017) The Effects of Hallucinogens on Gene Expression. Curr. Top. Behav. Neurosci. 36, 137– 158,  DOI: 10.1007/7854_2017_479
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      Vaidya, V. A., Marek, G. J., Aghajanian, G. K., and Duman, R. S. (1997) 5-HT2A receptor-mediated regulation of brain-derived neurotrophic factor mRNA in the hippocampus and the neocortex. J. Neurosci. 17, 2785– 2795,  DOI: 10.1523/JNEUROSCI.17-08-02785.1997
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      5-HT2A receptor-mediated regulation of brain-derived neurotrophic factor mRNA in the hippocampus and the neocortex
      Vaidya, Vidita A.; Marek, Gerard J.; Aghajanian, George K.; Duman, Ronald S.
      Journal of Neuroscience (1997), 17 (8), 2785-2795CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)
      The influence of 5-HT receptor agonists on the expression of BDNF in brain was detd. Administration of a hallucinogenic 5-HT2A/2C receptor agonist, but not a 5-HT1A receptor agonist, resulted in a significant but differential regulation of BDNF mRNA levels in hippocampus and neocortex. In the hippocampus, the 5-HT2A/2C receptor agonist significantly decreased BDNF mRNA expression in the dentate gyrus granule cell layer but did not influence expression of the neurotrophin in the CA subfields. In parietal cortex and other neocortical areas, but not piriform cortex, the 5-HT2A/2C receptor agonist dramatically increased the expression of BDNF mRNA. The effect of the 5-HT2A/2C receptor agonist on BDNF mRNA in both the hippocampus and the neocortex was blocked by pretreatment with a selective 5-HT2A, but not 5-HT2C, receptor antagonist. The expression of BDNF mRNA in the hippocampus is reported to be decreased by stress, raising the possibility that the 5-HT2A receptor mediates this effect. Pretreatment with ketanserin, a 5-HT2A/2C receptor antagonist, significantly blocked the stress-induced downregulation of BDNF mRNA in hippocampus, in support of this hypothesis. The results of this study raise the possibility that regulation of BDNF expression by hallucinogenic 5-HT2A receptor agonists leads to adaptations of synaptic strength in the hippocampus and the neocortex that may mediate some of the acute and long-term behavioral effects of these agents.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXisValtbo%253D&md5=5197609c1f783e1601924c5457a3b27b
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      Martin, D. A., Marona-Lewicka, D., Nichols, D. E., and Nichols, C. D. (2014) Chronic LSD alters gene expression profiles in the mPFC relevant to schizophrenia. Neuropharmacology 83, 1– 8,  DOI: 10.1016/j.neuropharm.2014.03.013
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      42
      Chronic LSD alters gene expression profiles in the mPFC relevant to schizophrenia
      Martin, David A.; Marona-Lewicka, Danuta; Nichols, David E.; Nichols, Charles D.
      Neuropharmacology (2014), 83 (), 1-8CODEN: NEPHBW; ISSN:0028-3908. (Elsevier B.V.)
      Chronic administration of lysergic acid diethylamide (LSD) every other day to rats results in a variety of abnormal behaviors. These build over the 90 day course of treatment and can persist at full strength for at least several months after cessation of treatment. The behaviors are consistent with those obsd. in animal models of schizophrenia and include hyperactivity, reduced sucrose-preference, and decreased social interaction. In order to elucidate mol. changes that underlie these aberrant behaviors, we chronically treated rats with LSD and performed RNA-sequencing on the medial prefrontal cortex (mPFC), an area highly assocd. with both the actions of LSD and the pathophysiol. of schizophrenia and other psychiatric illnesses. We obsd. widespread changes in the neurogenetic state of treated animals four weeks after cessation of LSD treatment. QPCR was used to validate a subset of gene expression changes obsd. with RNA-Seq, and confirmed a significant correlation between the two methods. Functional clustering anal. indicates differentially expressed genes are enriched in pathways involving neurotransmission (Drd2, Gabrb1), synaptic plasticity (Nr2a, Krox20), energy metab. (Atp5d, Ndufa1) and neuropeptide signaling (Npy, Bdnf), among others. Many processes identified as altered by chronic LSD are also implicated in the pathogenesis of schizophrenia, and genes affected by LSD are enriched with putative schizophrenia genes. Our results provide a relatively comprehensive anal. of mPFC transcriptional regulation in response to chronic LSD, and indicate that the long-term effects of LSD may bear relevance to psychiatric illnesses, including schizophrenia.
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    43. 43
      Griffiths, R. R., Richards, W. A., McCann, U., and Jesse, R. (2006) Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacol. (Berl) 187, 268– 294,  DOI: 10.1007/s00213-006-0457-5
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      43
      Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance
      Griffiths, R. R.; Richards, W. A.; McCann, U.; Jesse, R.
      Psychopharmacology (Berlin, Germany) (2006), 187 (3), 268-283CODEN: PSCHDL; ISSN:0033-3158. (Springer GmbH)
      Rationale Although psilocybin has been used for centuries for religious purposes, little is known scientifically about its acute and persisting effects. Objectives This double-blind study evaluated the acute and longer-term psychol. effects of a high dose of psilocybin relative to a comparison compd. administered under comfortable, supportive conditions. Materials and methods The participants were hallucinogen-naive adults reporting regular participation in religious or spiritual activities. Two or three sessions were conducted at 2-mo intervals. Thirty volunteers received orally administered psilocybin (30 mg/70 kg) and methylphenidate hydrochloride (40 mg/70 kg) in counterbalanced order. To obscure the study design, six addnl. volunteers received methylphenidate in the first two sessions and unblinded psilocybin in a third session. The 8-h sessions were conducted individually. Volunteers were encouraged to close their eyes and direct their attention inward. Study monitors rated volunteers' behavior during sessions. Volunteers completed questionnaires assessing drug effects and mystical experience immediately after and 2 mo after sessions. Community observers rated changes in the volunteer's attitudes and behavior. Results Psilocybin produced a range of acute perceptual changes, subjective experiences, and labile moods including anxiety. Psilocybin also increased measures of mystical experience. At 2 mo, the volunteers rated the psilocybin experience as having substantial personal meaning and spiritual significance and attributed to the experience sustained pos. changes in attitudes and behavior consistent with changes rated by community observers. Conclusions When administered under supportive conditions, psilocybin occasioned experiences similar to spontaneously occurring mystical experiences. The ability to occasion such experiences prospectively will allow rigorous scientific investigations of their causes and consequences.
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    44. 44
      Griffiths, R. R., Johnson, M. W., Richards, W. A., Richards, B. D., McCann, U., and Jesse, R. (2011) Psilocybin occasioned mystical-type experiences: immediate and persisting dose-related effects. Psychopharmacology 218, 649– 665,  DOI: 10.1007/s00213-011-2358-5
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      44
      Psilocybin occasioned mystical-type experiences: immediate and persisting dose-related effects
      Griffiths, Roland R.; Johnson, Matthew W.; Richards, William A.; Richards, Brian D.; McCann, Una; Jesse, Robert
      Psychopharmacology (Heidelberg, Germany) (2011), 218 (4), 649-665CODEN: PSCHDL; ISSN:0033-3158. (Springer)
      Rationale: This dose-effect study extends previous observations showing that psilocybin can occasion mystical-type experiences having persisting pos. effects on attitudes, mood, and behavior. Objectives: This double-blind study evaluated psilocybin (0, 5, 10, 20, 30 mg/70 kg, p.o.) administered under supportive conditions. Methods: Participants were 18 adults (17 hallucinogen-naive). Five 8-h sessions were conducted individually for each participant at 1-mo intervals. Participants were randomized to receive the four active doses in either ascending or descending order (nine participants each). Placebo was scheduled quasi-randomly. During sessions, volunteers used eyeshades and were instructed to direct their attention inward. Volunteers completed questionnaires assessing effects immediately after and 1 mo after each session, and at 14 mo follow-up. Results: Psilocybin produced acute perceptual and subjective effects including, at 20 and/or 30 mg/70 kg, extreme anxiety/fear (39% of volunteers) and/or mystical-type experience (72% of volunteers). One month after sessions at the two highest doses, volunteers rated the psilocybin experience as having substantial personal and spiritual significance, and attributed to the experience sustained pos. changes in attitudes, mood, and behavior, with the ascending dose sequence showing greater pos. effects. At 14 mo, ratings were undiminished and were consistent with changes rated by community observers. Both the acute and persisting effects of psilocybin were generally a monotonically increasing function of dose, with the lowest dose showing significant effects. Conclusions: Under supportive conditions, 20 and 30 mg/70 kg psilocybin occasioned mystical-type experiences having persisting pos. effects on attitudes, mood, and behavior. Implications for therapeutic trials are discussed.
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    45. 45
      Carhart-Harris, R. L. (2017) Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms. Sci. Rep. 7, 13817,  DOI: 10.1038/s41598-017-13282-7
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      Horsley, R. R., Pálenícek, T., Kolin, J., and Valeš, K. (2018) Psilocin and ketamine microdosing: effects of subchronic intermittent microdoses in the elevated plus-maze in male Wistar rats. Behav. Pharmacol. 29, 530– 536,  DOI: 10.1097/FBP.0000000000000394
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      46
      Psilocin and ketamine microdosing: effects of subchronic intermittent microdoses in the elevated plus-maze in male Wistar rats
      Horsley, Rachel R.; Palenicek, Tomas; Kolin, Jan; Vales, Karel
      Behavioural Pharmacology (2018), 29 (6), 530-536CODEN: BPHAEL; ISSN:0955-8810. (Lippincott Williams & Wilkins)
      Short-term moderate doses of serotonergic and dissociative hallucinogens can be useful in the treatment of anxiety. Recently, a trend has developed for long-term intermittent 'microdosing' (usually one-tenth of a 'full' active dose), with reports of long-lasting relief from anxiety and related disorders; however, there is no scientific evidence for the efficacy of therapeutic microdosing nor to show its lasting effects. The objective of this study was to test for lasting effects on anxiety in rats after microdosing with ketamine or psilocin. Over 6 days, Wistar rats (N=40) were administered ketamine (0.5 or 3 mg/kg), psilocin (0.05 or 0.075 mg/kg), or saline on three occasions. A 5-min elevated plus-maze test was conducted 48 h after the final drug treatment (n=8). Dependent variables were entries (frequency), spent time (%), and distance traveled (cm) in each zone, as well as total frequency of rears, stretch-attend postures, and head dips. Statistical analyses of drug effects used sep. independent one-way anal. of variance and pair-wise comparisons using independent t-tests. Statistical effects were modest or borderline and were most consistent with a mildly anxiogenic profile, which was significant at lower doses; however, this conclusion remains tentative. The lower doses of ketamine and psilocin produced comparable effects (to one another) across each variable, as did the higher doses. This pattern of effects may suggest a common (e.g. neurotransmitter/receptor) mechanism. We conclude that microdosing with hallucinogens for therapeutic purposes might be counter-productive; however, more research is needed to confirm our findings and to establish their translational relevance to clin. 'psychedelic' therapy.
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    47. 47
      Young, M. B., Andero, R., Ressler, K. J., and Howell, L. L. (2015) 3,4-Methylenedioxymethamphetamine facilitates fear extinction learning. Transl. Psychiatry 5, e634  DOI: 10.1038/tp.2015.138
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      3,4-Methylenedioxymethamphetamine facilitates fear extinction learning
      Young, M. B.; Andero, R.; Ressler, K. J.; Howell, L. L.
      Translational Psychiatry (2015), 5 (9), e634CODEN: TPRSCF; ISSN:2158-3188. (Nature Publishing Group)
      Acutely administered 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') has been proposed to have long-term pos. effects on post-traumatic stress disorder (PTSD) symptoms when combined with psychotherapy. No preclin. data support a mechanistic basis for these claims. Given the persistent nature of psychotherapeutic gains facilitated by MDMA, we hypothesized that MDMA improves fear extinction learning, a key process in exposure-based therapies for PTSD. In these expts., mice were first exposed to cued fear conditioning and treated with drug vehicle or MDMA before extinction training 2 days later. MDMA was administered systemically and also directly targeted to brain structures known to contribute to extinction. In addn. to behavioral measures of extinction, changes in mRNA levels of brain-derived neurotrophic factor (Bdnf) and Fos were measured after MDMA treatment and extinction. MDMA (7.8 mg kg-1) persistently and robustly enhanced long-term extinction when administered before extinction training. MDMA increased the expression of Fos in the amygdala and medial prefrontal cortex (mPFC), whereas increases in Bdnf expression were obsd. only in the amygdala after extinction training. Extinction enhancements were recapitulated when MDMA (1 μg) was infused directly into the basolateral complex of the amygdala (BLA), and enhancement was abolished when BDNF signaling was inhibited before extinction. These findings suggest that MDMA enhances fear memory extinction through a BDNF-dependent mechanism, and that MDMA may be a useful adjunct to exposure-based therapies for PTSD and other anxiety disorders characterized by altered fear learning.
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      Dunlap, L. E., Andrews, A. M., and Olson, D. E. (2018) Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine. ACS Chem. Neurosci. 9, 2408– 2427,  DOI: 10.1021/acschemneuro.8b00155
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      48
      Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine
      Dunlap, Lee E.; Andrews, Anne M.; Olson, David E.
      ACS Chemical Neuroscience (2018), 9 (10), 2408-2427CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
      Better known as "ecstasy", 3,4-methylenedioxymethamphetamine (MDMA) is a small mol. that has played a prominent role in defining the ethos of today's teenagers and young adults, much like lysergic acid diethylamide (LSD) did in the 1960s. Though MDMA possesses structural similarities to compds. like amphetamine and mescaline, it produces subjective effects that are unlike any of the classical psychostimulants or hallucinogens and is one of the few compds. capable of reliably producing prosocial behavioral states. As a result, MDMA has captured the attention of recreational users, the media, artists, psychiatrists, and neuropharmacologists alike. Here, we detail the synthesis of MDMA as well as its pharmacol., metab., adverse effects, and potential use in medicine. Finally, we discuss its history and why it is perhaps the most important compd. for the future of psychedelic science-having the potential to either facilitate new psychedelic research initiatives, or to usher in a second Dark Age for the field.
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    49. 49
      Sitaram, B. R., Lockett, L., Talomsin, R., Blackman, G. L., and McLeod, W. R. (1987) In vivo metabolism of 5-methoxy-N,N-dimethyltryptamine and N,N-dimethyltryptamine in the rat. Biochem. Pharmacol. 36, 1509– 1512,  DOI: 10.1016/0006-2952(87)90118-3
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      49
      In vivo metabolism of 5-methoxy-N,N-dimethyltryptamine and N,N-dimethyltryptamine in the rat
      Sitaram, Balvant R.; Lockett, Lynn; Talomsin, Rerngjit; Blackman, Graeme L.; McLeod, William R.
      Biochemical Pharmacology (1987), 36 (9), 1509-12CODEN: BCPCA6; ISSN:0006-2952.
      Following i.p. administration, 5-methoxy-N,N-dimethyltryptamine and N,N-dimethyltryptamine are subject to both a very rapid uptake into, and clearance from, all tissues examd. The current studies in vivo confirm previous in vitro observations that the routes involved in the metab. of these compds. include oxidative deamination, N-demethylation, O-demethylation, and N-oxidn. The anal. of metabolic profiles in various tissues led to the identification of the N-oxides as major metabolites. The successful inhibition and redirection of metab. away from the indole acids towards the parent compds. and their structurally unique metabolites were demonstrated in animals pretreated with iproniazid.
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    50. 50
      Muschamp, J. W., Regina, M. J., Hull, E. M., Winter, J. C., and Rabin, R. A. (2004) Lysergic acid diethylamide and [-]-2,5-dimethoxy-4-methylamphetamine increase extracellular glutamate in rat prefrontal cortex. Brain Res. 1023, 134– 140,  DOI: 10.1016/j.brainres.2004.07.044
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      Lysergic acid diethylamide and [-]-2,5-dimethoxy-4-methylamphetamine increase extracellular glutamate in rat prefrontal cortex
      Muschamp, John W.; Regina, Meredith J.; Hull, Elaine M.; Winter, Jerrold C.; Rabin, Richard A.
      Brain Research (2004), 1023 (1), 134-140CODEN: BRREAP; ISSN:0006-8993. (Elsevier B.V.)
      The ability of hallucinogens to increase extracellular glutamate in the prefrontal cortex (PFC) was assessed by in vivo microdialysis. The hallucinogen lysergic acid diethylamide (LSD; 0.1 mg/kg, i.p.) caused a time-dependent increase in PFC glutamate that was blocked by the 5-HT2A antagonist M100907 (0.05 mg/kg, i.p.). Similarly, the 5-HT2A/C agonist [-]-2,5-dimethoxy-4-methylamphetamine (DOM; 0.6 mg/kg, i.p.), which is a phenethylamine hallucinogen, increased glutamate to 206% above saline-treated controls. When LSD (10 μM) was directly applied to the PFC by reverse dialysis, a rapid increase in PFC glutamate levels was obsd. Glutamate levels in the PFC remained elevated after the drug infusion was discontinued. These data provide direct evidence in vivo for the hypothesis that an enhanced release of glutamate is a common mechanism in the action of hallucinogens.
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      Bouso, J. C. (2015) Long-Term Use of Psychedelic Drugs Is Associated with Differences in Brain Structure and Personality in Humans. Eur. Neuropsychopharmacol. 25, 483– 492,  DOI: 10.1016/j.euroneuro.2015.01.008
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      Long-term use of psychedelic drugs is associated with differences in brain structure and personality in humans
      Bouso, Jose Carlos; Palhano-Fontes, Fernanda; Rodriguez-Fornells, Antoni; Ribeiro, Sidarta; Sanches, Rafael; Crippa, Jose Alexandre S.; Hallak, Jaime E. C.; de Araujo, Draulio B.; Riba, Jordi
      European Neuropsychopharmacology (2015), 25 (4), 483-492CODEN: EURNE8; ISSN:0924-977X. (Elsevier B.V.)
      Psychedelic agents have a long history of use by humans for their capacity to induce profound modifications in perception, emotion and cognitive processes. Despite increasing knowledge of the neural mechanisms involved in the acute effects of these drugs, the impact of sustained psychedelic use on the human brain remains largely unknown. Mol. pharmacol. studies have shown that psychedelic 5-hydroxytryptamine (5HT)2A agonists stimulate neurotrophic and transcription factors assocd. with synaptic plasticity. These data suggest that psychedelics could potentially induce structural changes in brain tissue. Here we looked for differences in cortical thickness (CT) in regular users of psychedelics. We obtained magnetic resonance imaging (MRI) images of the brains of 22 regular users of ayahuasca (a prepn. whose active principle is the psychedelic 5HT2A agonist N,N-dimethyltryptamine (DMT)) and 22 controls matched for age, sex, years of education, verbal IQ and fluid IQ. Ayahuasca users showed significant CT differences in midline structures of the brain, with thinning in the posterior cingulate cortex (PCC), a key node of the default mode network. CT values in the PCC were inversely correlated with the intensity and duration of prior use of ayahuasca and with scores on self-transcendence, a personality trait measuring religiousness, transpersonal feelings and spirituality. Although direct causation cannot be established, these data suggest that regular use of psychedelic drugs could potentially lead to structural changes in brain areas supporting attentional processes, self-referential thought, and internal mentation. These changes could underlie the previously reported personality changes in long-term users and highlight the involvement of the PCC in the effects of psychedelics.
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      Bouso, J. C. (2012) Personality, psychopathology, life attitudes and neuropsychological performance among ritual users of Ayahuasca: a longitudinal study. PLoS One 7, e42421  DOI: 10.1371/journal.pone.0042421
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      Personality, psychopathology, life attitudes and neuropsychological performance among ritual users of ayahuasca: a longitudinal study
      Bouso, Jose Carlos; Gonzalez, Debora; Fondevila, Sabela; Cutchet, Marta; Fernandez, Xavier; Barbosa, Paulo Cesar Ribeiro; Alcazar-Corcoles, Miguel Angel; Araujo, Wladimyr Sena; Barbanoj, Manel J.; Fabregas, Josep Maria; Riba, Jordi
      PLoS One (2012), 7 (8), e42421CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
      Ayahuasca is an Amazonian psychoactive plant beverage contg. the serotonergic 5-HT2A agonist N,N-dimethyltryptamine (DMT) and monoamine oxidase-inhibiting alkaloids (harmine, harmaline and tetrahydroharmine) that render it orally active. Ayahuasca ingestion is a central feature in several Brazilian syncretic churches that have expanded their activities to urban Brazil, Europe and North America. Members of these groups typically ingest ayahuasca at least twice per mo. Prior research has shown that acute ayahuasca increases blood flow in prefrontal and temporal brain regions and that it elicits intense modifications in thought processes, perception and emotion. However, regular ayahuasca use does not seem to induce the pattern of addiction-related problems that characterize drugs of abuse. To study the impact of repeated ayahuasca use on general psychol. well-being, mental health and cognition, here we assessed personality, psychopathol., life attitudes and neuropsychol. performance in regular ayahuasca users (n = 127) and controls (n = 115) at baseline and 1 yr later. Controls were actively participating in non-ayahuasca religions. Users showed higher Reward Dependence and Self-Transcendence and lower Harm Avoidance and Self-Directedness. They scored significantly lower on all psychopathol. measures, showed better performance on the Stroop test, the Wisconsin Card Sorting Test and the Letter-No. Sequencing task from the WAIS-III, and better scores on the Frontal Systems Behavior Scale. Anal. of life attitudes showed higher scores on the Spiritual Orientation Inventory, the Purpose in Life Test and the Psychosocial Well-Being test. Despite the lower no. of participants available at follow-up, overall differences with controls were maintained one year later. In conclusion, we found no evidence of psychol. maladjustment, mental health deterioration or cognitive impairment in the ayahuasca-using group.
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      Marona-Lewicka, D., Nichols, C. D., and Nichols, D. E. (2011) An Animal Model of Schizophrenia Based on Chronic LSD Administration: Old Idea, New Results. Neuropharmacology 61, 503– 512,  DOI: 10.1016/j.neuropharm.2011.02.006
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      An animal model of schizophrenia based on chronic LSD administration: Old idea, new results
      Marona-Lewicka, Danuta; Nichols, Charles D.; Nichols, David E.
      Neuropharmacology (2011), 61 (3), 503-512CODEN: NEPHBW; ISSN:0028-3908. (Elsevier B.V.)
      Many people who take LSD experience a second temporal phase of LSD intoxication that is qual. different, and was described by Daniel Freedman as "clearly a paranoid state. " We have previously shown that the discriminative stimulus effects of LSD in rats also occur in two temporal phases, with initial effects mediated by activation of 5-HT2A receptors (LSD30), and the later temporal phase mediated by dopamine D2-like receptors (LSD90). Surprisingly, we have now found that non-competitive NMDA antagonists produced full substitution in LSD90 rats, but only in older animals, whereas in LSD30, or in younger animals, these drugs did not mimic LSD. Chronic administration of low doses of LSD (>3 mo, 0.16 mg/kg every other day) induces a behavioral state characterized by hyperactivity and hyperirritability, increased locomotor activity, anhedonia, and impairment in social interaction that persists at the same magnitude for at least three months after cessation of LSD treatment. These behaviors, which closely resemble those assocd. with psychosis in humans, are not induced by withdrawal from LSD; rather, they are the result of neuroadaptive changes occurring in the brain during the chronic administration of LSD. These persistent behaviors are transiently reversed by haloperidol and olanzapine, but are insensitive to MDL-100907. Gene expression anal. data show that chronic LSD treatment produced significant changes in multiple neurotransmitter system-related genes, including those for serotonin and dopamine. Thus, we propose that chronic treatment of rats with low doses of LSD can serve as a new animal model of psychosis that may mimic the development and progression of schizophrenia, as well as model the established disease better than current acute drug administration models utilizing amphetamine or NMDA antagonists such as PCP.
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      Buchborn, T., Schröder, H., Höllt, V., and Grecksch, G. (2014) Repeated lysergic acid diethylamide in an animal model of depression: Normalisation of learning behaviour and hippocampal serotonin 5-HT2 signalling. J. Psychopharmacol. 28, 545– 552,  DOI: 10.1177/0269881114531666
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      Repeated lysergic acid diethylamide in an animal model of depression: normalisation of learning behaviour and hippocampal serotonin 5-HT2 signalling
      Buchborn, Tobias; Schroeder, Helmut; Hoellt, Volker; Grecksch, Gisela
      Journal of Psychopharmacology (London, United Kingdom) (2014), 28 (6), 545-552, 8 pp.CODEN: JOPSEQ; ISSN:0269-8811. (Sage Publications Ltd.)
      A re-balance of postsynaptic serotonin (5-HT) receptor signalling, with an increase in 5-HT1A and a decrease in 5-HT2A signalling, is a final common pathway multiple antidepressants share. Given that the 5-HT1A/2A agonist lysergic acid diethylamide (LSD), when repeatedly applied, selectively downregulates 5-HT2A, but not 5-HT1A receptors, one might expect LSD to similarly re-balance the postsynaptic 5-HT signalling. Challenging this idea, we use an animal model of depression specifically responding to repeated antidepressant treatment (olfactory bulbectomy), and test the antidepressant-like properties of repeated LSD treatment (0.13 mg/kg/d, 11 d). In line with former findings, we observe that bulbectomized rats show marked deficits in active avoidance learning. These deficits, similarly as we earlier noted with imipramine, are largely reversed by repeated LSD administration. Addnl., bulbectomized rats exhibit distinct anomalies of monoamine receptor signalling in hippocampus and/or frontal cortex; from these, only the hippocampal decrease in 5-HT2 related [35S]-GTP-gamma-S binding is normalized by LSD. Importantly, the sham-operated rats do not profit from LSD, and exhibit reduced hippocampal 5-HT2 signalling. As behavioral deficits after bulbectomy respond to agents classified as antidepressants only, we conclude that the effect of LSD in this model can be considered antidepressant-like, and discuss it in terms of a re-balance of hippocampal 5-HT2/5-HT1A signalling.
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    55. 55
      González-Maeso, J., Ebersole, B. J., Wurmbach, E., Lira, A., Zhou, M., Weisstaub, N., Hen, R., Gingrich, J. A., and Sealfon, S. C. (2003) Transcriptome Fingerprints Distinguish Hallucinogenic and Nonhallucinogenic 5-Hydroxytryptamine 2A Receptor Agonist Effects in Mouse Somatosensory Cortex. J. Neurosci. 23, 8836– 8843,  DOI: 10.1523/JNEUROSCI.23-26-08836.2003
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      Transcriptome fingerprints distinguish hallucinogenic and nonhallucinogenic 5-hydroxytryptamine 2A receptor agonist effects in mouse somatosensory cortex
      Gonzalez-Maeso, Javier; Yuen, Tony; Ebersole, Barbara J.; Wurmbach, Elisa; Lira, Alena; Zhou, Mingming; Weisstaub, Noelia; Hen, Rene; Gingrich, Jay A.; Sealfon, Stuart C.
      Journal of Neuroscience (2003), 23 (26), 8836-8843CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)
      Most neuropharmacol. agents and many drugs of abuse modulate the activity of heptahelical G-protein-coupled receptors. Although the effects of these ligands result from changes in cellular signaling, their neurobehavioral activity may not correlate with results of in vitro signal transduction assays. 5-Hydroxytryptamine 2A receptor (5-HT2AR) partial agonists that have similar pharmacol. profiles differ in the behavioral responses they elicit. In vitro studies suggest that different agonists acting at the same receptor may establish distinct patterns of signal transduction. Testing this hypothesis in the brain requires a global signal transduction assay that is applicable in vivo. To distinguish the cellular effects of the different 5-HT2AR agonists, we developed an assay for global signal transduction on the basis of high throughput quantification of rapidly modulated transcripts. Study of the responses to agonists in human embryonic kidney 293 cells stably expressing 5-HT2ARs demonstrated that each agonist elicits a distinct transcriptome fingerprint. We therefore studied behavioral and cortical signal transduction responses in wild-type and 5-HT2AR null-mutant mice. The hallucinogenic chems. (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) and lysergic acid diethylamide (LSD) stimulated a head-twitch behavioral response that was not obsd. with the nonhallucinogenic lisuride hydrogen maleate (LHM) and was absent in receptor null-mutant mice. We also found that DOI, LSD, and LHM each induced distinct transcriptome fingerprints in somatosensory cortex that were absent in 5-HT2AR null-mutants. Moreover, DOI and LSD showed similarities in the transcriptome fingerprints obtained that were not obsd. with the behaviorally inactive drug LHM. Our results demonstrate that chems. acting at the 5-HT2AR induced specific cellular response patterns in vivo that are reflected in unique changes in the somatosensory cortex transcriptome.
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      Vaidya, V. A., Marek, G. J., Aghajanian, G. K., and Duman, R. S. (1997) 5-HT2A receptor-mediated regulation of brain-derived neurotrophic factor mRNA in the hippocampus and the neocortex. J. Neurosci. 17, 2785– 2795,  DOI: 10.1523/JNEUROSCI.17-08-02785.1997
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      5-HT2A receptor-mediated regulation of brain-derived neurotrophic factor mRNA in the hippocampus and the neocortex
      Vaidya, Vidita A.; Marek, Gerard J.; Aghajanian, George K.; Duman, Ronald S.
      Journal of Neuroscience (1997), 17 (8), 2785-2795CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)
      The influence of 5-HT receptor agonists on the expression of BDNF in brain was detd. Administration of a hallucinogenic 5-HT2A/2C receptor agonist, but not a 5-HT1A receptor agonist, resulted in a significant but differential regulation of BDNF mRNA levels in hippocampus and neocortex. In the hippocampus, the 5-HT2A/2C receptor agonist significantly decreased BDNF mRNA expression in the dentate gyrus granule cell layer but did not influence expression of the neurotrophin in the CA subfields. In parietal cortex and other neocortical areas, but not piriform cortex, the 5-HT2A/2C receptor agonist dramatically increased the expression of BDNF mRNA. The effect of the 5-HT2A/2C receptor agonist on BDNF mRNA in both the hippocampus and the neocortex was blocked by pretreatment with a selective 5-HT2A, but not 5-HT2C, receptor antagonist. The expression of BDNF mRNA in the hippocampus is reported to be decreased by stress, raising the possibility that the 5-HT2A receptor mediates this effect. Pretreatment with ketanserin, a 5-HT2A/2C receptor antagonist, significantly blocked the stress-induced downregulation of BDNF mRNA in hippocampus, in support of this hypothesis. The results of this study raise the possibility that regulation of BDNF expression by hallucinogenic 5-HT2A receptor agonists leads to adaptations of synaptic strength in the hippocampus and the neocortex that may mediate some of the acute and long-term behavioral effects of these agents.
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      Smith, R. L., Canton, H., Barrett, R. J., and Sanders-Bush, E. (1998) Agonist properties of N,N-dimethyltryptamine at serotonin 5-HT2A and 5-HT2C receptors. Pharmacol., Biochem. Behav. 61, 323– 30,  DOI: 10.1016/S0091-3057(98)00110-5
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      Agonist properties of N,N-dimethyltryptamine at serotonin 5-HT2A and 5-HT2C receptors
      Smith, Randy L.; Canton, Herve; Barrett, Robert J.; Sanders-Bush, Elaine
      Pharmacology, Biochemistry and Behavior (1998), 61 (3), 323-330CODEN: PBBHAU; ISSN:0091-3057. (Elsevier Science Inc.)
      Extensive behavioral and biochem. evidence suggests an agonist role at the 5-HT2A receptor, and perhaps the 5-HT2C receptor, in the mechanism of action of hallucinogenic drugs. However the published in vitro pharmacol. properties of N,N-dimethyltryptamine (DMT), an hallucinogenic tryptamine analog, are not consistent with this hypothesis. We, therefore, undertook an extensive investigation into the properties of DMT at 5-HT2A and 5-HT2C receptors. In fibroblasts transfected with the 5-HT2A receptor or the 5-HT2C receptor, DMT activated the major intracellular signaling pathway (phosphoinositide hydrolysis) to an extent comparable to that produced by serotonin. Because drug efficacy changes with receptor d. and cellular micro-environment, we also examd. the properties of DMT in native prepns. using a behavioral and biochem. approach. Rats were trained to discriminate an antagonist ketanserin from an agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) in a two-lever choice paradigm. Pharmacol. studies showed that responding on the DOI and ketanserin lever reflected agonist and antagonist activity at 5-HT2A receptors, and hence, was a suitable model for evaluating the in vivo functional properties of DMT. Like other 5-HT2A receptor agonists, DMT substituted fully for DOI. Intact choroid plexus was used to evaluate the agonist properties at endogenous 5-HT2C receptors; DMT was a partial agonist at 5-HT2C receptors in this native prepn. Thus, we conclude that DMT behaves as an agonist at both 5-HT2A and 5-HT2A receptors. One difference was evident in that the 5-HT2C, but not the 5-HT2A, receptor showed a profound desensitization to DMT over time. This difference is interesting in light of the recent report that the hallucinogenic activity of DMT does not tolerate in humans and suggests the 5-HT2C receptor plays a less prominent role in the action of DMT.
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    58. 58
      Strassman, R. J., Qualls, C. R., and Berg, L. M. (1996) Differential tolerance to biological and subjective effects of four closely spaced doses of N,N-dimethyltryptamine in humans. Biol. Psychiatry 39, 784– 795,  DOI: 10.1016/0006-3223(95)00200-6
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      Differential tolerance to biological and subjective effects of four closely spaced doses of N,N-dimethyltryptamine in humans
      Strassman, Rick J.; Qualls, Clifford R.; Berg, Laura M.
      Biological Psychiatry (1996), 39 (9), 784-795CODEN: BIPCBF; ISSN:0006-3223. (Elsevier)
      Tolerance to the behavioral effects of the short-acting, endogenous hallucinogen, N,N-dimethyltryptamine (DMT) is seen inconsistently in animals, and has not been produced in humans. The nature and time course of responses to repetitive, closely spaced administrations of an hallucinogenic dose of DMT were characterized. Thirteen experienced hallucinogen users received i.v. 0.3 mg/kg DMT fumarate, or saline placebo, four times, at 30 min intervals, on 2 sep. days, in a randomized, double-blind, design. Tolerance to "psychedelic" subjective effects did not occur according to either clin. interview or Hallucinogen Rating Scale scores. Adrenocorticotropic hormone (ACTH), prolactin, cortisol, and heart rate responses decreased with repeated DMT administration, although blood pressure did not. These data demonstrate the unique properties of DMT relative to other hallucinogens and underscore the differential regulation of the multiple processes mediating the effects of DMT.
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      Duman, R. S. and Monteggia, L. M. (2006) A Neurotrophic Model for Stress-Related Mood Disorders. Biol. Psychiatry 59, 1116– 1127,  DOI: 10.1016/j.biopsych.2006.02.013
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      A Neurotrophic Model for Stress-Related Mood Disorders
      Duman, Ronald S.; Monteggia, Lisa M.
      Biological Psychiatry (2006), 59 (12), 1116-1127CODEN: BIPCBF; ISSN:0006-3223. (Elsevier Inc.)
      A review. There is a growing body of evidence demonstrating that stress decreases the expression of brain-derived neurotrophic factor (BDNF) in limbic structures that control mood and that antidepressant treatment reverses or blocks the effects of stress. Decreased levels of BDNF, as well as other neruotrophic factors, could contribute to the atrophy of certain limbic structures, including the hippocampus and prefrontal cortex that has been obsd. in depressed subjects. Conversely, the neurotrophic actions of antidepressants could reverse neuronal atrophy and cell loss and thereby contribute to the therapeutic actions of these treatments. This review provides a crit. examn. of the neurotrophic hypothesis of depression that has evolved from this work, including anal. of preclin. cellular (adult neurogenesis) and behavioral models of depression and antidepressant actions, as well as clin. neuroimaging and postmortem studies. Although there are some limitations, the results of these studies are consistent with the hypothesis that decreased expression of BDNF and possibly other growth factors contributes to depression and that upregulation of BDNF plays a role in the actions of antidepressant treatment.
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    60. 60
      Santos, A. F. A., Vieira, A. L. S., Pic-Taylor, A., and Caldas, E. D. (2017) Reproductive effects of the psychoactive beverage ayahuasca in male Wistar rats after chronic exposure. Rev. Bras. Farmacogn. 27, 353– 360,  DOI: 10.1016/j.bjp.2017.01.006
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      Reproductive effects of the psychoactive beverage ayahuasca in male Wistar rats after chronic exposure
      Santos, Alana de Fatima Andrade; Vieira, Ana Luiza Sarkis; Pic-Taylor, Aline; Caldas, Eloisa Dutra
      Revista Brasileira de Farmacognosia (2017), 27 (3), 353-360CODEN: RBFAEL; ISSN:0102-695X. (Elsevier Editora Ltda.)
      Ayahuasca is a psychoactive beverage used ancestrally by indigenous Amazonian tribes and, more recently, by Christian religions in Brazil and other countries. This study aimed to investigate the reproductive effects of this beverage in male Wistar rats after chronic exposure. The rats were treated by gavage every other day for 70 days at 0 (control), 1×, 2×, 4× and 8× the dose used in a religious ritual (12 animals per group), and animals euthanized on the 71st day. Compared to controls, there was a significant decrease in food consumption and body wt. gain in rats from the 4× and 8× groups, and a significant increase in the brain and stomach relative wt. at the 8× group. There was a significant increase in total serum testosterone, and a decrease in spermatic transit time and spermatic reserves in the epididymis caudae in the 4× group, but not in the highest dose group. No significant changes were found in the other reproductive endpoints (spermatozoid motility and morphol., total spermatozoid count and daily sperm prodn.), and histol. of testis and epididymis. This study identified a no-obsd.-adverse-effect-level for chronic and reproductive effects of ayahuasca in male Wistar rats at 2× the ritualistic dose, which corresponds in this study to 0.62 mg/kg bw N,N-dimethyltryptamine, 6.6 mg/kg bw harmine and 0.52 mg/kg bw harmaline. A potential toxic effect of ayahuasca in male rats was obsd. at the 4× dose, with a non-monotonic dose-response. Studies investigating the role of ayahuasca components in regulating testosterone levels are needed to better understand this action.
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    61. 61
      Schreiber, R., Selbach, K., Asmussen, M., Hesse, D., and de Vry, J. (2000) Effects of serotonin1/2 receptor agonists on dark-phase food and water intake in rats. Pharmacol., Biochem. Behav. 67, 291– 305,  DOI: 10.1016/S0091-3057(00)00357-9
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      Effects of serotonin1/2 receptor agonists on dark-phase food and water intake in rats
      Schreiber, R.; Selbach, K.; Asmussen, M.; Hesse, D.; de Vry, J.
      Pharmacology, Biochemistry and Behavior (2000), 67 (2), 291-305CODEN: PBBHAU; ISSN:0091-3057. (Elsevier Science Inc.)
      The effects of serotonin (5-hydroxytryptamine, 5-HT)1/2 receptor agonists for 5-HT1 and 5-HT2 receptors on dark-phase ingestive behavior were evaluated in 12-h food-deprived, female Wistar rats. The amt. of food and water consumed after 1, 2, 6 and 12 h was measured. The following agonists were tested: ipsapirone [preferred 5-HT receptor(s) and dose range in mg/kg, IP: 5-HT1A and 3-30, resp.], CP-94,253 (5-HT1B; 0.3-3), TFMPP (5-HT1B/2C; 0.3-10), m-CPP (5-HT2C/1B; 0.3-10), ORG 37684 (5-HT2C; 0.3-10), BW 723C86 (5-HT2B; 3-30) and DOI (5-HT2A/2C; 0.3-3). Ipsapirone induced hyperphagia during the first hour of food access and hypophagia during the last interval. All other compds. induced dose- and time-dependent hypophagia. M-CPP and TFMPP induced the most marked redn. of food intake and were the only drugs inducing rebound hyperphagia. Except for m-CPP and TFMPP, effects on food intake could generally be dissocd. from effects on water intake. The receptor profile of the compds. tested suggests that stimulation of 5-HT1B, 5-HT2C, 5-HT2A or 5-HT2B receptors results in hypophagia. As the less selective agonists were the more potent anorexics, it is suggested that simultaneous activation of these receptors results in synergistic effects on ingestive behavior. Addnl. antagonism studies are required to ascertain the proposed role of particular 5-HT receptor subtypes in the hypophagic effects of the tested compds.
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    62. 62
      Winden, K. D., Ebrahimi-Fakhari, D., and Sahin, M. (2018) Abnormal mTOR Activation in Autism. Annu. Rev. Neurosci. 41, 1– 23,  DOI: 10.1146/annurev-neuro-080317-061747
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      Abnormal mTOR Activation in Autism
      Winden, Kellen D.; Ebrahimi-Fakhari, Darius; Sahin, Mustafa
      Annual Review of Neuroscience (2018), 41 (), 1-23CODEN: ARNSD5; ISSN:0147-006X. (Annual Reviews)
      The mechanistic target of rapamycin (mTOR) is an important signaling hub that integrates environmental information regarding energy availability and stimulates anabolic mol. processes and cell growth. Abnormalities in this pathway have been identified in several syndromes in which autism spectrum disorder (ASD) is highly prevalent. Several studies have investigated mTOR signaling in developmental and neuronal processes that, when dysregulated, could contribute to the development of ASD. Although many potential mechanisms still remain to be fully understood, these assocns. are of great interest because of the clin. availability of mTOR inhibitors. Clin. trials evaluating the efficacy of mTOR inhibitors to improve neurodevelopmental outcomes have been initiated.
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      Cai, Z., Zhou, Y., He, W., Xiao, M., and Yan, L. J. (2015) Activation of mTOR: a culprit of Alzheimer’s disease?. Neuropsychiatr. Dis. Treat. 11, 1015– 1030,  DOI: 10.2147/NDT.S75717
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      Activation of mTOR: a culprit of Alzheimer's disease?
      Cai, Zhiyou; Chen, Guanghui; He, Wenbo; Xiao, Ming; Yan, Liang-Jun
      Neuropsychiatric Disease and Treatment (2015), 11 (), 1015-1030CODEN: NDTEAZ; ISSN:1178-2021. (Dove Medical Press Ltd.)
      Alzheimer's disease (AD) is characterized by cognitive impairment in clin. presentation, and by β-amyloid (Aβ) prodn. and the hyper-phosphorylation of tau in basic research. More highlights demonstrate that the activation of the mammalian target of rapamycin (mTOR) enhances Aβ generation and deposition by modulating amyloid precursor protein (APP) metab. and upregulating β- and γ-secretases. mTOR, an inhibitor of autophagy, decreases Aβ clearance by scissoring autophagy function. mTOR regulates Aβ generation or Aβ clearance by regulating several key signaling pathways, including phosphoinositide 3-kinase (PI3-K)/protein kinase B (Akt), glycogen synthase kinase 3 [GSK-3], AMP-activated protein kinase (AMPK), and insulin/insulin-like growth factor 1 (IGF-1). The activation of mTOR is also a contributor to aberrant hyperphosphorylated tau. Rapamycin, the inhibitor of mTOR, may mitigate cognitive impairment and inhibit the pathologies assocd. with amyloid plaques and neurofibrillary tangles by promoting autophagy. Furthermore, the upstream and downstream components of mTOR signaling are involved in the pathogenesis and progression of AD. Hence, inhibiting the activation of mTOR may be an important therapeutic target for AD.
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    64. 64
      Amat, J., Dolzani, S. D., Tilden, S., Christianson, J. P., Kubala, K. H., Bartholomay, K., Sperr, K., Ciancio, N., Watkins, L. R., and Maier, S. F. (2016) Previous Ketamine Produces an Enduring Blockade of Neurochemical and Behavioral Effects of Uncontrollable Stress. J. Neurosci. 36, 153– 161,  DOI: 10.1523/JNEUROSCI.3114-15.2016
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      64
      Previous ketamine produces an enduring blockade of neurochemical and behavioral effects of uncontrollable stress
      Amat, Jose; Dolzani, Samuel D.; Tilden, Scott; Christianson, John P.; Kubala, Kenneth H.; Bartholomay, Kristi; Sperr, Katherine; Ciancio, Nicholas; Watkins, Linda R.; Maier, Steven F.
      Journal of Neuroscience (2016), 36 (1), 153-161CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)
      Recent interest in the antidepressant and anti-stress effects of subanesthetic doses of ketamine, an NMDA receptor antagonist, has identified mechanisms whereby ketamine reverses the effect of stress, but little is known regarding the prophylactic effect ketamine might have on future stressors. Here we investigate the prophylactic effect of ketamine against neurochem. and behavioral changes that follow inescapable, uncontrollable tail shocks (ISs) in Sprague Dawley rats. IS induces increased anxiety, which is dependent on activation of serotonergic (5-HT) dorsal raphe nucleus (DRN) neurons that project to the basolateral amygdala (BLA). Ketamine (10 mg/kg, i.p.) administered 2 h, 1 wk, or 2 wk before IS prevented the increased extracellular levels of 5-HT in the BLA typically produced by IS. In addn., ketamine administered at these time points blocked the decreased juvenile social investigation produced by IS. Microinjection of ketamine into the prelimbic (PL) region of the medial prefrontal cortex duplicated the effects of systemic ketamine, and, conversely, systemic ketamine effects were prevented by pharmacol. inhibition of the PL. Although IS does not activate DRN-projecting neurons from the PL, IS did so after ketamine, suggesting that the prophylactic effect of ketamine is a result of altered functioning of this projection.
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      McGowan, J. C., LaGamma, C. T., Lim, S. C., Tsitsiklis, M., Neria, Y., Brachman, R. A., and Denny, C. A. (2017) Prophylactic Ketamine Attenuates Learned Fear. Neuropsychopharmacology 42, 1577– 1589,  DOI: 10.1038/npp.2017.19
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      Prophylactic Ketamine Attenuates Learned Fear
      McGowan, Josephine C.; LaGamma, Christina T.; Lim, Sean C.; Tsitsiklis, Melina; Neria, Yuval; Brachman, Rebecca A.; Denny, Christine A.
      Neuropsychopharmacology (2017), 42 (8), 1577-1589CODEN: NEROEW; ISSN:0893-133X. (Nature Publishing Group)
      Ketamine has been reported to be an efficacious antidepressant for major depressive disorder and posttraumatic stress disorder. Most recently, ketamine has also been shown to be prophylactic against stress-induced depressive-like behavior in mice. It remains unknown, however, when ketamine should be administered relative to a stressor in order to maximize its antidepressant and/or prophylactic effects. Moreover, it is unknown whether ketamine can be prophylactic against subsequent stressors. We systematically administered ketamine at different time points relative to a fear experience, in order to det. when ketamine is most effective at reducing fear expression or preventing fear reactivation. Using a contextual fear conditioning (CFC) paradigm, mice were administered a single dose of saline or ketamine (30 mg/kg) at varying time points before or after CFC. Mice administered prophylactic ketamine 1 wk, but not 1 mo or 1 h before CFC, exhibited reduced freezing behavior when compared with mice administered saline. In contrast, ketamine administration following CFC or during extinction did not alter subsequent fear expression. However, ketamine administered before reinstatement increased the no. of rearing bouts in an open field, possibly suggesting an increase in attentiveness. These data indicate that ketamine can buffer a fear response when given a week before as prophylactic, but not when given immediately before or after a stress-inducing episode. Thus, ketamine may be most useful in the clinic if administered in a prophylactic manner 1 wk before a stressor, in order to protect against heightened fear responses to aversive stimuli.
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    66. 66
      Brachman, R. A. (2016) Ketamine as a Prophylactic Against Stress-Induced Depressive-like Behavior. Biol. Psychiatry 79, 776– 786,  DOI: 10.1016/j.biopsych.2015.04.022
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      66
      Ketamine as a Prophylactic Against Stress-Induced Depressive-Like Behavior
      Brachman, Rebecca A.; McGowan, Josephine C.; Perusini, Jennifer N.; Lim, Sean C.; Pham, Thu Ha; Faye, Charlene; Gardier, Alain M.; Mendez-David, Indira; David, Denis J.; Hen, Rene; Denny, Christine A.
      Biological Psychiatry (2016), 79 (9), 776-786CODEN: BIPCBF; ISSN:0006-3223. (Elsevier)
      Stress exposure is one of the greatest risk factors for psychiatric illnesses like major depressive disorder and posttraumatic stress disorder. However, not all individuals exposed to stress develop affective disorders. Stress resilience, the ability to experience stress without developing persistent psychopathol., varies from individual to individual. Enhancing stress resilience in at-risk populations could potentially protect against stress-induced psychiatric disorders. Despite this fact, no resilience-enhancing pharmaceuticals have been identified. Using a chronic social defeat (SD) stress model, learned helplessness (LH), and a chronic corticosterone (CORT) model in mice, we tested if ketamine could protect against depressive-like behavior. Mice were administered a single dose of saline or ketamine and then 1 wk later were subjected to 2 wk of SD, LH training, or 3 wk of CORT. SD robustly and reliably induced depressive-like behavior in control mice. Mice treated with prophylactic ketamine were protected against the deleterious effects of SD in the forced swim test and in the dominant interaction test. We confirmed these effects in LH and the CORT model. In the LH model, latency to escape was increased following training, and this effect was prevented by ketamine. In the CORT model, a single dose of ketamine blocked stress-induced behavior in the forced swim test, novelty suppressed feeding paradigm, and the sucrose splash test. These data show that ketamine can induce persistent stress resilience and, therefore, may be useful in protecting against stress-induced disorders.
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    67. 67
      Dunlap, L. E. and Olson, D. E. (2018) Reaction of N,N-Dimethyltryptamine with Dichloromethane Under Common Experimental Conditions. ACS Omega 3, 4968– 4973,  DOI: 10.1021/acsomega.8b00507
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      Reaction of N,N-Dimethyltryptamine with Dichloromethane Under Common Experimental Conditions
      Dunlap, Lee E.; Olson, David E.
      ACS Omega (2018), 3 (5), 4968-4973CODEN: ACSODF; ISSN:2470-1343. (American Chemical Society)
      A large no. of clin. used drugs and exptl. pharmaceuticals possess the N,N-dimethyltryptamine (DMT) structural core. Previous reports have described the reaction of this motif with dichloromethane (DCM), a common lab. solvent used during extn. and purifn., leading to the formation of an undesired quaternary ammonium salt byproduct. However, the kinetics of this reaction under various conditions have not been thoroughly described. Here, we report a series of expts. designed to simulate the exposure of DMT to DCM that would take place during extn. from plant material, biphasic aq. work-up, or column chromatog. purifn. We find that the quaternary ammonium salt byproduct forms at an exceedingly slow rate, only accumulates to a significant extent upon prolonged exposure of DMT to DCM, and is readily extd. into water. Our results suggest that DMT can be exposed to DCM under conditions where contact times are limited (<30 min) with minimal risk of degrdn. and that this byproduct is not obsd. following aq. extn. However, alternative solvents should be considered when the exptl. conditions require longer contact times. Our work has important implications for prepg. a wide-range of pharmaceuticals bearing the DMT structural motif in high yields and purities.
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    68. 68
      Shumake, J., Furgeson-Moreira, S., and Monfils, M. H. (2014) Predictability and heritability of individual differences in fear learning. Anim. Cogn. 17, 1207– 1221,  DOI: 10.1007/s10071-014-0752-1
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      68
      Predictability and heritability of individual differences in fear learning
      Shumake Jason; Furgeson-Moreira Sergio; Monfils Marie H
      Animal cognition (2014), 17 (5), 1207-21 ISSN:.
      Our objective was to characterize individual differences in fear conditioning and extinction in an outbred rat strain, to test behavioral predictors of these individual differences, and to assess their heritability. We fear-conditioned 100 Long-Evans rats, attempted to extinguish fear the next day, and tested extinction recall on the third day. The distribution of freezing scores after fear conditioning was skewed, with most rats showing substantial freezing; after fear extinction, the distribution was bimodal with most rats showing minimal freezing, but a substantial portion showing maximal freezing. Longer rearing episodes measured prior to conditioning predicted less freezing at the beginning of extinction, but differences in extinction learning were not predicted by any baseline exploratory behaviors. We tested the heritability of extinction differences by breeding rats from the top and bottom 20% of freezing scores during extinction recall. We then ran the offspring through the same conditioning/extinction procedure, with the addition of recording ultrasonic vocalizations throughout training and testing. Only a minority of rats emitted distress vocalizations during fear acquisition, but the incidence was less frequent in the offspring of good extinguishers than in poor extinguishers or randomly bred controls. The occurrence of distress vocalizations during acquisition predicted higher levels of freezing during fear recall regardless of breeding line, but the relationship between vocalization and freezing was no longer evident following extinction training, at which point freezing levels were influenced only by breeding and not by vocalization. The heritability (h(2)) of extinction recall was estimated at 0.36, consistent with human estimates.
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      Benjamini, Y. and Hochberg, Y. (1995) Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing. Journal of the Royal Statistical Society. Series B (Methodological) 57, 289– 300,  DOI: 10.1111/j.2517-6161.1995.tb02031.x
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