ACS Publications. Most Trusted. Most Cited. Most Read
Metabolism and Distribution of Clozapine-N-oxide: Implications for Nonhuman Primate Chemogenetics

OR SEARCH CITATIONS

My Activity
Publications

Figure 1Loading Img
Download Hi-Res ImageDownload to MS-PowerPointCite This:ACS Chem. Neurosci. 2017, 8, 7, 1570-1576
    Research Article

    Metabolism and Distribution of Clozapine-N-oxide: Implications for Nonhuman Primate Chemogenetics
    Click to copy article linkArticle link copied!

    View Author Information
    † Yerkes National Primate Research Center, Atlanta, Georgia 30329, United States
    ‡ Sano Informed Prescribing, Inc. Franklin, Tennessee 37067, United States
    § Department of Psychiatry and Behavioral Sciences, School of Medicine, Emory University, Atlanta, Georgia 30322, United States
    ∥ Department of Psychology, Emory University, Atlanta, Georgia 30322, United States
    ⊥ Department of Neurology, School of Medicine, Emory University, Atlanta, Georgia 30322, United States
    # Udall Center of Excellence for Parkinson’s Disease Research, Emory University, Atlanta, Georgia 30329, United States
    *Jessica Raper, Ph.D. Mailing address: Yerkes National Primate Research Center, 954 Gatewood Rd NE, Atlanta, GA 30329. E-mail address: [email protected]. Phone: 404-727-8334.
    Other Access Options

    ACS Chemical Neuroscience

    Cite this: ACS Chem. Neurosci. 2017, 8, 7, 1570–1576
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acschemneuro.7b00079
    Published March 21, 2017
    Copyright © 2017 American Chemical Society
    Request reuse permissions

    Abstract

    Click to copy section linkSection link copied!
    Abstract Image

    The use of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in neuroscience has rapidly expanded in rodent studies but has lagged behind in nonhuman primate (NHP) experiments, slowing the development of this method for therapeutic use in humans. One reason for the slow adoption of DREADD technology in primates is that the pharmacokinetic properties and bioavailability of clozapine-n-oxide (CNO), the most commonly used ligand for human muscarinic (hM) DREADDs, are not fully described in primates. We report an extensive pharmacokinetic study using subcutaneous (SC) administration of CNO in five adult rhesus monkeys. CNO reached maximal plasma and cerebrospinal fluid (CSF) concentrations within 2 h after injection, with an observed dose-dependent increase in levels following a 3 and 10 mg/kg SC dose. Since CSF concentrations were below values predicted from unbound plasma concentrations, we investigated whether CNO was restricted from the CNS through active transport at the blood–brain barrier. In vitro assessment demonstrated that CNO is a substrate for P-glycoprotein (Pgp; efflux ratio, 20), thus providing a likely mechanism limiting CNO levels in the CNS. Furthermore, CNO is metabolized to the psychoactive compounds clozapine and n-desmethylclozapine in monkeys. The concentrations of clozapine detected in the CSF are sufficient to activate several types of receptor (including the hM-DREADDs). Our results suggest that CNO metabolism and distribution may interfere with reproducibility and interpretation of DREADD-related experiments in NHPs and calls for a re-evaluation of the use of CNO in DREADD-related experiments in NHPs along with the need to test alternative compounds.

    Copyright © 2017 American Chemical Society

    Subjects

    what are subjects

    Keywords

    what are keywords

    Read this article

    To access this article, please review the available access options below.

    Get instant access

    Purchase Access

    Read this article for 48 hours. Check out below using your ACS ID or as a guest.

    Recommended

    Access through Your Institution

    You may have access to this article through your institution.

    Your institution does not have access to this content. Add or change your institution or let them know you’d like them to include access.

    Cited By

    Click to copy section linkSection link copied!

    This article is cited by 79 publications.

    1. Jessica Raper, Mark A. G. Eldridge, Scott M. Sternson, Jalene Y. Shim, Grace P. Fomani, Barry J. Richmond, Thomas Wichmann, Adriana Galvan. Characterization of Ultrapotent Chemogenetic Ligands for Research Applications in Nonhuman Primates. ACS Chemical Neuroscience 2022, 13 (21) , 3118-3125. https://doi.org/10.1021/acschemneuro.2c00525
    2. Karen J. Thompson, Elham Khajehali, Sophie J. Bradley, Jovana S. Navarrete, Xi Ping Huang, Samuel Slocum, Jian Jin, Jing Liu, Yan Xiong, Reid H. J. Olsen, Jeffrey F. Diberto, Kristen M. Boyt, Melanie M. Pina, Dipanwita Pati, Colin Molloy, Christoffer Bundgaard, Patrick M. Sexton, Thomas L. Kash, Michael J. Krashes, Arthur Christopoulos, Bryan L. Roth, Andrew B. Tobin. DREADD Agonist 21 Is an Effective Agonist for Muscarinic-Based DREADDs in Vitro and in Vivo. ACS Pharmacology & Translational Science 2018, 1 (1) , 61-72. https://doi.org/10.1021/acsptsci.8b00012
    3. Marvin Villacrez, Karin Hellman, Tatsuya Ono, Yutaka Sugihara, Melinda Rezeli, Fredrik Ek, Gyorgy Marko-Varga, Roger Olsson. Evaluation of Drug Exposure and Metabolism in Locust and Zebrafish Brains Using Mass Spectrometry Imaging. ACS Chemical Neuroscience 2018, 9 (8) , 1994-2000. https://doi.org/10.1021/acschemneuro.7b00459
    4. Craig W. Lindsley (Editor-in-Chief), Kathryn A. Cunningham (Associate Editor), Jacob M. Hooker (Associate Editor), Anne M. Andrews (Associate Editor). Editors’ Favorites of 2017. ACS Chemical Neuroscience 2018, 9 (1) , 1-4. https://doi.org/10.1021/acschemneuro.8b00001
    5. Faisal Alosaimi, Yasin Temel, Ali Jahanshahi. Assessing the role of globus pallidus externa in relaying the effect of subthalamic nucleus high-frequency stimulation on the dorsal raphe nucleus. Deep Brain Stimulation 2025, 8 , 1-5. https://doi.org/10.1016/j.jdbs.2024.12.002
    6. Quynh-Anh Nguyen, Peter M. Klein, Cheng Xie, Katelyn N. Benthall, Jillian Iafrati, Jesslyn Homidan, Jacob T. Bendor, Barna Dudok, Jordan S. Farrell, Tilo Gschwind, Charlotte L. Porter, Annahita Keravala, G. Steven Dodson, Ivan Soltesz. Acetylcholine receptor based chemogenetics engineered for neuronal inhibition and seizure control assessed in mice. Nature Communications 2024, 15 (1) https://doi.org/10.1038/s41467-024-44853-8
    7. Catherine Elorette, Atsushi Fujimoto, Frederic M. Stoll, Satoka H. Fujimoto, Niranjana Bienkowska, Liza London, Lazar Fleysher, Brian E. Russ, Peter H. Rudebeck. The neural basis of resting-state fMRI functional connectivity in fronto-limbic circuits revealed by chemogenetic manipulation. Nature Communications 2024, 15 (1) https://doi.org/10.1038/s41467-024-49140-0
    8. Yu-Bo Hu, Xi Deng, Lu Liu, Can-Can Cao, Ya-Wen Su, Zhen-Jie Gao, Xin Cheng, Deshan Kong, Qi Li, Yan-Wei Shi, Xiao-Guang Wang, Xiaojing Ye, Hu Zhao. Distinct roles of excitatory and inhibitory neurons in the medial prefrontal cortex in the expression and reconsolidation of methamphetamine-associated memory in male mice. Neuropsychopharmacology 2024, 49 (12) , 1827-1838. https://doi.org/10.1038/s41386-024-01879-2
    9. Philip J. Clark, Zachary D. Brodnik, Rodrigo A. España. Chemogenetic Signaling in Space and Time: Considerations for Designing Neuroscience Experiments Using DREADDs. The Neuroscientist 2024, 30 (3) , 328-346. https://doi.org/10.1177/10738584221134587
    10. Namrata Tiwari, Cristina Smith, Divya Sharma, Shanwei Shen, Parshva Mehta, Liya Y. Qiao. Plp1-expresssing perineuronal DRG cells facilitate colonic and somatic chronic mechanical pain involving Piezo2 upregulation in DRG neurons. Cell Reports 2024, 43 (5) , 114230. https://doi.org/10.1016/j.celrep.2024.114230
    11. Bojana Kokinovic, Patricia Seja, Angelica Donati, Maria Ryazantseva, Alban de Kerchove d’Exaerde, Serge N. Schiffmann, Tomi Taira, Svetlana M. Molchanova. Spontaneous activity of striatal projection neurons supports maturation of striatal inputs to substantia nigra dopaminergic neurons. 2024https://doi.org/10.7554/eLife.96574
    12. Bojana Kokinovic, Patricia Seja, Angelica Donati, Maria Ryazantseva, Alban de Kerchove d’Exaerde, Serge N. Schiffmann, Tomi Taira, Svetlana M. Molchanova. Spontaneous activity of striatal projection neurons supports maturation of striatal inputs to substantia nigra dopaminergic neurons. 2024https://doi.org/10.7554/eLife.96574.1
    13. Jiayi Cheng, Bowen Zhang, Wenjun Cai, Siqing Zhao, Xiaoyun Deng, Baofeng Wang, Xiaohua Zhu, Yingying Lv, Wenzhen Zhu, Xiaoqing Zhang, Hong Chen, Ling Liu. Engineering of Rhesus Monkey Pluripotent Stem Cells for Noninvasive Survey and Remote Control after Brain Allotransplantation. Fundamental Research 2024, 282 https://doi.org/10.1016/j.fmre.2024.03.003
    14. Ellen Kingston, Malcolm Tingle, Brandi L. Bellissima, Nuala Helsby, Kathryn Burns. CYP-catalysed cycling of clozapine and clozapine- N -oxide promotes the generation of reactive oxygen species in vitro. Xenobiotica 2024, 54 (1) , 26-37. https://doi.org/10.1080/00498254.2023.2294473
    15. Yoshiatsu Aomine, Yoshinobu Oyama, Koki Sakurai, Tom Macpherson, Takaaki Ozawa, Takatoshi Hikida. Clozapine N-oxide, compound 21, and JHU37160 do not influence effortful reward-seeking behavior in mice. Psychopharmacology 2024, 241 (1) , 89-96. https://doi.org/10.1007/s00213-023-06465-w
    16. Zengmin Li, Dilsher Athwal, Hsu-Lei Lee, Pankaj Sah, Patricio Opazo, Kai-Hsiang Chuang. Locating causal hubs of memory consolidation in spontaneous brain network in male mice. Nature Communications 2023, 14 (1) https://doi.org/10.1038/s41467-023-41024-z
    17. Jimena Perez-Sanchez, Steven J. Middleton, Luke A. Pattison, Helen Hilton, Mosab Ali Awadelkareem, Sana R. Zuberi, Maria B. Renke, Huimin Hu, Xun Yang, Alex J. Clark, Ewan St. John Smith, David L. Bennett. A humanized chemogenetic system inhibits murine pain-related behavior and hyperactivity in human sensory neurons. Science Translational Medicine 2023, 15 (716) https://doi.org/10.1126/scitranslmed.adh3839
    18. Kate A. Lawson, Christina M. Ruiz, Stephen V. Mahler. A head-to-head comparison of two DREADD agonists for suppressing operant behavior in rats via VTA dopamine neuron inhibition. Psychopharmacology 2023, 240 (10) , 2101-2110. https://doi.org/10.1007/s00213-023-06429-0
    19. Janine Traut, Jose Prius Mengual, Elise J Meijer, Laura E McKillop, Hannah Alfonsa, Anna Hoerder-Suabedissen, Seo Ho Song, Kristoffer D Fehér, Dieter Riemann, Zoltan Molnar, Colin J Akerman, Vladyslav V Vyazovskiy, Lukas B Krone. Effects of clozapine-N-oxide and compound 21 on sleep in laboratory mice. eLife 2023, 12 https://doi.org/10.7554/eLife.84740
    20. Gessynger Morais-Silva, Rianne R. Campbell, Hyungwoo Nam, Mahashweta Basu, Marco Pagliusi, Megan E. Fox, C. Savio Chan, Sergio D. Iñiguez, Seth Ament, Nathan Cramer, Marcelo Tadeu Marin, Mary Kay Lobo. Molecular, Circuit, and Stress Response Characterization of Ventral Pallidum Npas1-Neurons. The Journal of Neuroscience 2023, 43 (3) , 405-418. https://doi.org/10.1523/JNEUROSCI.0971-22.2022
    21. Adriana K. Cushnie, Daniel N. Bullock, Ana M.G. Manea, Wei Tang, Jan Zimmermann, Sarah R. Heilbronner. The use of chemogenetic actuator ligands in nonhuman primate DREADDs-fMRI. Current Research in Neurobiology 2023, 4 , 100072. https://doi.org/10.1016/j.crneur.2022.100072
    22. Peiqing Guan, Chunzheng Huang, Qinghui Lan, Shile Huang, Peiling Zhou, Changzheng Zhang. Activation of ventral tegmental area dopaminergic neurons ameliorates anxiety-like behaviors in single prolonged stress-induced PTSD model rats. Neurochemistry International 2022, 161 , 105424. https://doi.org/10.1016/j.neuint.2022.105424
    23. Taku Hasegawa, Satomi Chiken, Kenta Kobayashi, Atsushi Nambu. Subthalamic nucleus stabilizes movements by reducing neural spike variability in monkey basal ganglia. Nature Communications 2022, 13 (1) https://doi.org/10.1038/s41467-022-29750-2
    24. Pratik Kumar, Luke D. Lavis. Melding Synthetic Molecules and Genetically Encoded Proteins to Forge New Tools for Neuroscience. Annual Review of Neuroscience 2022, 45 (1) , 131-150. https://doi.org/10.1146/annurev-neuro-110520-030031
    25. Alzahraa Amer, John H. Martin. Repeated motor cortex theta-burst stimulation produces persistent strengthening of corticospinal motor output and durable spinal cord structural changes in the rat. Brain Stimulation 2022, 15 (4) , 1013-1022. https://doi.org/10.1016/j.brs.2022.07.005
    26. Jessica Raper, Adriana Galvan. Applications of chemogenetics in non-human primates. Current Opinion in Pharmacology 2022, 64 , 102204. https://doi.org/10.1016/j.coph.2022.102204
    27. Danique Jeurissen, S. Shushruth, Yasmine El-Shamayleh, Gregory D. Horwitz, Michael N. Shadlen. Deficits in decision-making induced by parietal cortex inactivation are compensated at two timescales. Neuron 2022, 110 (12) , 1924-1931.e5. https://doi.org/10.1016/j.neuron.2022.03.022
    28. Zachary A. Rodd, Eric A. Engleman, William A. Truitt, Andrew R. Burke, Andrei I. Molosh, Richard L. Bell, Sheketha R. Hauser. CNO Administration Increases Dopamine and Glutamate in the Medial Prefrontal Cortex of Wistar Rats: Further Concerns for the Validity of the CNO-activated DREADD Procedure. Neuroscience 2022, 491 , 176-184. https://doi.org/10.1016/j.neuroscience.2022.03.028
    29. Siobhan Gee, David Taylor. Alternative Routes of Administration of Clozapine. CNS Drugs 2022, 36 (2) , 105-111. https://doi.org/10.1007/s40263-022-00900-w
    30. Yael S. Grossman, Clementine Fillinger, Alessia Manganaro, George Voren, Rachel Waldman, Tiffany Zou, William G. Janssen, Paul J. Kenny, Dani Dumitriu. Structure and function differences in the prelimbic cortex to basolateral amygdala circuit mediate trait vulnerability in a novel model of acute social defeat stress in male mice. Neuropsychopharmacology 2022, 47 (3) , 788-799. https://doi.org/10.1038/s41386-021-01229-6
    31. Shwan B. Javdan, Tara L. Deans. Design and development of engineered receptors for cell and tissue engineering. Current Opinion in Systems Biology 2021, 28 , 100363. https://doi.org/10.1016/j.coisb.2021.100363
    32. Patrick H. Roseboom, Sascha A.L. Mueller, Jonathan A. Oler, Andrew S. Fox, Marissa K. Riedel, Victoria R. Elam, Miles E. Olsen, Juan L. Gomez, Matthew A. Boehm, Alexandra H. DiFilippo, Bradley T. Christian, Michael Michaelides, Ned H. Kalin. Evidence in primates supporting the use of chemogenetics for the treatment of human refractory neuropsychiatric disorders. Molecular Therapy 2021, 29 (12) , 3484-3497. https://doi.org/10.1016/j.ymthe.2021.04.021
    33. Mineki Oguchi, Shingo Tanaka, Xiaochuan Pan, Takefumi Kikusui, Keiko Moriya-Ito, Shigeki Kato, Kazuto Kobayashi, Masamichi Sakagami. Chemogenetic inactivation reveals the inhibitory control function of the prefronto-striatal pathway in the macaque brain. Communications Biology 2021, 4 (1) https://doi.org/10.1038/s42003-021-02623-y
    34. Xuefeng Yan, Sanjay Telu, Rachel M Dick, Jeih-San Liow, Paolo Zanotti-Fregonara, Cheryl L Morse, Lester S Manly, Robert L Gladding, Stal Shrestha, Walter Lerchner, Yuji Nagai, Takafumi Minamimoto, Sami S Zoghbi, Robert B Innis, Victor W Pike, Barry J Richmond, Mark AG Eldridge. [ 11 C]deschloroclozapine is an improved PET radioligand for quantifying a human muscarinic DREADD expressed in monkey brain. Journal of Cerebral Blood Flow & Metabolism 2021, 41 (10) , 2571-2582. https://doi.org/10.1177/0271678X211007949
    35. Nathan W. Burnham, Corryn N. Chaimowitz, Cortland C. Vis, Ana Paula Segantine Dornellas, Montserrat Navarro, Todd E. Thiele. Lateral hypothalamus-projecting noradrenergic locus coeruleus pathway modulates binge-like ethanol drinking in male and female TH-ires-cre mice. Neuropharmacology 2021, 196 , 108702. https://doi.org/10.1016/j.neuropharm.2021.108702
    36. Jaroslawna Meister, Lei Wang, Sai P. Pydi, Jürgen Wess. Chemogenetic approaches to identify metabolically important GPCR signaling pathways: Therapeutic implications. Journal of Neurochemistry 2021, 158 (3) , 603-620. https://doi.org/10.1111/jnc.15314
    37. Akihiko Ozawa, Hiroyuki Arakawa. Chemogenetics drives paradigm change in the investigation of behavioral circuits and neural mechanisms underlying drug action. Behavioural Brain Research 2021, 406 , 113234. https://doi.org/10.1016/j.bbr.2021.113234
    38. Matthew A. Boehm, Jordi Bonaventura, Juan L. Gomez, Oscar Solís, Elliot A. Stein, Charles W. Bradberry, Michael Michaelides. Translational PET applications for brain circuit mapping with transgenic neuromodulation tools. Pharmacology Biochemistry and Behavior 2021, 204 , 173147. https://doi.org/10.1016/j.pbb.2021.173147
    39. Zhengri Li, Song Hee Lee, Hee Jin Jeong, Hee Eun Kang. Pharmacokinetic changes of clozapine and norclozapine in a rat model of non-alcoholic fatty liver disease induced by orotic acid. Xenobiotica 2021, 51 (3) , 324-334. https://doi.org/10.1080/00498254.2020.1851070
    40. Marc Deffains, Tho Haï Nguyen, Hugues Orignac, Nathalie Biendon, Sandra Dovero, Erwan Bezard, Thomas Boraud. In vivo electrophysiological validation of DREADD‐based modulation of pallidal neurons in the non‐human primate. European Journal of Neuroscience 2021, 53 (7) , 2192-2204. https://doi.org/10.1111/ejn.14746
    41. Lei Wang, Lu Zhu, Jaroslawna Meister, Derek B.J. Bone, Sai P. Pydi, Mario Rossi, Jürgen Wess. Use of DREADD Technology to Identify Novel Targets for Antidiabetic Drugs. Annual Review of Pharmacology and Toxicology 2021, 61 (1) , 421-440. https://doi.org/10.1146/annurev-pharmtox-030220-121042
    42. Machi Horiai, Ayano Otsuka, Shizu Hidema, Yuichi Hiraoka, Ryotaro Hayashi, Shinji Miyazaki, Tamio Furuse, Hiroaki Mizukami, Ryoichi Teruyama, Masaru Tamura, Haruhiko Bito, Yuko Maejima, Kenju Shimomura, Katsuhiko Nishimori. Targeting oxytocin receptor (Oxtr)-expressing neurons in the lateral septum to restore social novelty in autism spectrum disorder mouse models. Scientific Reports 2020, 10 (1) https://doi.org/10.1038/s41598-020-79109-0
    43. Tian-Yuan Luo, Shuang Cai, Zai-Xun Qin, Shao-Cheng Yang, Yue Shu, Cheng-Xi Liu, Yu Zhang, Lin Zhang, Liang Zhou, Tian Yu, Shou-Yang Yu. Basal Forebrain Cholinergic Activity Modulates Isoflurane and Propofol Anesthesia. Frontiers in Neuroscience 2020, 14 https://doi.org/10.3389/fnins.2020.559077
    44. Nicholas A. Upright, Mark G. Baxter. Effect of chemogenetic actuator drugs on prefrontal cortex-dependent working memory in nonhuman primates. Neuropsychopharmacology 2020, 45 (11) , 1793-1798. https://doi.org/10.1038/s41386-020-0660-9
    45. Yuji Nagai, Naohisa Miyakawa, Hiroyuki Takuwa, Yukiko Hori, Kei Oyama, Bin Ji, Manami Takahashi, Xi-Ping Huang, Samuel T. Slocum, Jeffrey F. DiBerto, Yan Xiong, Takuya Urushihata, Toshiyuki Hirabayashi, Atsushi Fujimoto, Koki Mimura, Justin G. English, Jing Liu, Ken-ichi Inoue, Katsushi Kumata, Chie Seki, Maiko Ono, Masafumi Shimojo, Ming-Rong Zhang, Yutaka Tomita, Jin Nakahara, Tetsuya Suhara, Masahiko Takada, Makoto Higuchi, Jian Jin, Bryan L. Roth, Takafumi Minamimoto. Deschloroclozapine, a potent and selective chemogenetic actuator enables rapid neuronal and behavioral modulations in mice and monkeys. Nature Neuroscience 2020, 23 (9) , 1157-1167. https://doi.org/10.1038/s41593-020-0661-3
    46. Julia Huey, Kaya Keutler, Carsten Schultz. Chemical Biology Toolbox for Studying Pancreatic Islet Function – A Perspective. Cell Chemical Biology 2020, 27 (8) , 1015-1031. https://doi.org/10.1016/j.chembiol.2020.07.023
    47. Mayank Aggarwal, Yumiko Akamine, Andrew W. Liu, Jeffery R. Wickens. The nucleus accumbens and inhibition in the ventral tegmental area play a causal role in the Kamin blocking effect. European Journal of Neuroscience 2020, 52 (3) , 3087-3109. https://doi.org/10.1111/ejn.14732
    48. J. Megan Fredericks, Kiana E. Dash, Emilia M. Jaskot, Thomas W. Bennett, Walter Lerchner, George Dold, David Ide, Alexander C. Cummins, Violette H. Der Minassian, Janita N. Turchi, Barry J. Richmond, Mark A.G. Eldridge. Methods for mechanical delivery of viral vectors into rhesus monkey brain. Journal of Neuroscience Methods 2020, 339 , 108730. https://doi.org/10.1016/j.jneumeth.2020.108730
    49. Annette Pisanski, Xiuqing Ding, Nils A Koch, Silvia Pagliardini. Chemogenetic modulation of the parafacial respiratory group influences the recruitment of abdominal activity during REM sleep. Sleep 2020, 43 (5) https://doi.org/10.1093/sleep/zsz283
    50. Ken Berglund, Alejandra M. Fernandez, Claire‐Anne N. Gutekunst, Ute Hochgeschwender, Robert E. Gross. Step‐function luminopsins for bimodal prolonged neuromodulation. Journal of Neuroscience Research 2020, 98 (3) , 422-436. https://doi.org/10.1002/jnr.24424
    51. Lore M. Peeters, Stephan Missault, Aneta J. Keliris, Georgios A. Keliris. Combining designer receptors exclusively activated by designer drugs and neuroimaging in experimental models: A powerful approach towards neurotheranostic applications. British Journal of Pharmacology 2020, 177 (5) , 992-1002. https://doi.org/10.1111/bph.14885
    52. Sandesh Panthi, Beulah Leitch. The impact of silencing feed-forward parvalbumin-expressing inhibitory interneurons in the cortico-thalamocortical network on seizure generation and behaviour. Neurobiology of Disease 2019, 132 , 104610. https://doi.org/10.1016/j.nbd.2019.104610
    53. Jordi Bonaventura, Mark A. G. Eldridge, Feng Hu, Juan L. Gomez, Marta Sanchez-Soto, Ara M. Abramyan, Sherry Lam, Matthew A. Boehm, Christina Ruiz, Mitchell R. Farrell, Andrea Moreno, Islam Mustafa Galal Faress, Niels Andersen, John Y. Lin, Ruin Moaddel, Patrick J. Morris, Lei Shi, David R. Sibley, Stephen V. Mahler, Sadegh Nabavi, Martin G. Pomper, Antonello Bonci, Andrew G. Horti, Barry J. Richmond, Michael Michaelides. High-potency ligands for DREADD imaging and activation in rodents and monkeys. Nature Communications 2019, 10 (1) https://doi.org/10.1038/s41467-019-12236-z
    54. Martin Jendryka, Monika Palchaudhuri, Daniel Ursu, Bastiaan van der Veen, Birgit Liss, Dennis Kätzel, Wiebke Nissen, Anton Pekcec. Pharmacokinetic and pharmacodynamic actions of clozapine-N-oxide, clozapine, and compound 21 in DREADD-based chemogenetics in mice. Scientific Reports 2019, 9 (1) https://doi.org/10.1038/s41598-019-41088-2
    55. Sarah Mondoloni, Romain Durand-de Cuttoli, Alexandre Mourot. Cell-Specific Neuropharmacology. Trends in Pharmacological Sciences 2019, 40 (9) , 696-710. https://doi.org/10.1016/j.tips.2019.07.007
    56. Jessica Raper, Lauren Murphy, Rebecca Richardson, Zoe Romm, Zsofia Kovacs-Balint, Christa Payne, Adriana Galvan. Chemogenetic Inhibition of the Amygdala Modulates Emotional Behavior Expression in Infant Rhesus Monkeys. eneuro 2019, 6 (5) , ENEURO.0360-19.2019. https://doi.org/10.1523/ENEURO.0360-19.2019
    57. Avinash R. Vaidya, Maia S. Pujara, Michael Petrides, Elisabeth A. Murray, Lesley K. Fellows. Lesion Studies in Contemporary Neuroscience. Trends in Cognitive Sciences 2019, 23 (8) , 653-671. https://doi.org/10.1016/j.tics.2019.05.009
    58. Vena K. Martinez, Fatima Saldana-Morales, Jenny J. Sun, Ping Jun Zhu, Mauro Costa-Mattioli, Russell S. Ray. Off-Target Effects of Clozapine-N-Oxide on the Chemosensory Reflex Are Masked by High Stress Levels. Frontiers in Physiology 2019, 10 https://doi.org/10.3389/fphys.2019.00521
    59. . Binding Profile, Metabolism, Kinetics, Drug Interactions and Use of Plasma Levels. 2019, 90-113. https://doi.org/10.1017/9781108553575.007
    60. Christopher J. Magnus, Peter H. Lee, Jordi Bonaventura, Roland Zemla, Juan L. Gomez, Melissa H. Ramirez, Xing Hu, Adriana Galvan, Jayeeta Basu, Michael Michaelides, Scott M. Sternson. Ultrapotent chemogenetics for research and potential clinical applications. Science 2019, 364 (6436) https://doi.org/10.1126/science.aav5282
    61. Andreas Bay Kønig, Chiara Ciriachi, Ulrik Gether, Mattias Rickhag. Chemogenetic Targeting of Dorsomedial Direct-pathway Striatal Projection Neurons Selectively Elicits Rotational Behavior in Mice. Neuroscience 2019, 401 , 106-116. https://doi.org/10.1016/j.neuroscience.2019.01.013
    62. Yifeng Cheng, Jun Wang. The use of chemogenetic approaches in alcohol use disorder research and treatment. Alcohol 2019, 74 , 39-45. https://doi.org/10.1016/j.alcohol.2018.05.012
    63. Korin E. Leffler, Abdel A. Abdel-Rahman. Estrogen-Dependent Disruption of Adiponectin-Connexin43 Signaling Underlies Exacerbated Myocardial Dysfunction in Diabetic Female Rats. Journal of Pharmacology and Experimental Therapeutics 2019, 368 (2) , 208-217. https://doi.org/10.1124/jpet.118.254029
    64. Daicia C. Allen, Timothy L. Carlson, Yan Xiong, Jian Jin, Kathleen A. Grant, Verginia C. Cuzon Carlson. A Comparative Study of the Pharmacokinetics of Clozapine N-Oxide and Clozapine N-Oxide Hydrochloride Salt in Rhesus Macaques. The Journal of Pharmacology and Experimental Therapeutics 2019, 368 (2) , 199-207. https://doi.org/10.1124/jpet.118.252031
    65. Patrick Aldrin-Kirk, Tomas Björklund. Practical Considerations for the Use of DREADD and Other Chemogenetic Receptors to Regulate Neuronal Activity in the Mammalian Brain. 2019, 59-87. https://doi.org/10.1007/978-1-4939-9065-8_4
    66. Daniel F. Manvich, Kevin A. Webster, Stephanie L. Foster, Martilias S. Farrell, James C. Ritchie, Joseph H. Porter, David Weinshenker. The DREADD agonist clozapine N-oxide (CNO) is reverse-metabolized to clozapine and produces clozapine-like interoceptive stimulus effects in rats and mice. Scientific Reports 2018, 8 (1) https://doi.org/10.1038/s41598-018-22116-z
    67. Lucia Schoderboeck, Hollie E. Wicky, Wickliffe C. Abraham, Stephanie M. Hughes. Genetic Targeting and Chemogenetic Inhibition of Newborn Neurons. Human Gene Therapy Methods 2018, 29 (6) , 259-268. https://doi.org/10.1089/hgtb.2018.182
    68. Tansi Khodai, Nicolas Nunn, Amy A. Worth, Claire H. Feetham, Mino D. C. Belle, Hugh D. Piggins, Simon M. Luckman. PACAP Neurons in the Ventromedial Hypothalamic Nucleus Are Glucose Inhibited and Their Selective Activation Induces Hyperglycaemia. Frontiers in Endocrinology 2018, 9 https://doi.org/10.3389/fendo.2018.00632
    69. Safa Bouabid, Fu‐Ming Zhou. Cyclic AMP ‐producing chemogenetic activation of indirect pathway striatal projection neurons and the downstream effects on the globus pallidus and subthalamic nucleus in freely moving mice. Journal of Neurochemistry 2018, 145 (6) , 436-448. https://doi.org/10.1111/jnc.14331
    70. Poonam B. Jaiswal, Olivia C. Mistretta, Patricia J. Ward, Arthur W. English. Chemogenetic Enhancement of Axon Regeneration Following Peripheral Nerve Injury in the SLICK-A Mouse. Brain Sciences 2018, 8 (5) , 93. https://doi.org/10.3390/brainsci8050093
    71. Erin J Campbell, Nathan J Marchant. The use of chemogenetics in behavioural neuroscience: receptor variants, targeting approaches and caveats. British Journal of Pharmacology 2018, 175 (7) , 994-1003. https://doi.org/10.1111/bph.14146
    72. Stefania Bellini, Kelsey E. Fleming, Modhurika De, John P. McCauley, Maurice A. Petroccione, Lianna Y. D'Brant, Artem Tkachenko, SoYoung Kwon, Lindsey A. Jones, Annalisa Scimemi. Neuronal Glutamate Transporters Control Dopaminergic Signaling and Compulsive Behaviors. The Journal of Neuroscience 2018, 38 (4) , 937-961. https://doi.org/10.1523/JNEUROSCI.1906-17.2017
    73. Christophe Varin, Patricia Bonnavion. Pharmacosynthetic Deconstruction of Sleep-Wake Circuits in the Brain. 2018, 153-206. https://doi.org/10.1007/164_2018_183
    74. Ben Korin, Asya Rolls. Application of Chemogenetics and Optogenetics to Dissect Brain-Immune Interactions. 2018, 195-208. https://doi.org/10.1007/978-1-4939-7828-1_11
    75. Patrick Aldrin-Kirk, Andreas Heuer, Daniella Rylander Ottosson, Marcus Davidsson, Bengt Mattsson, Tomas Björklund. Chemogenetic modulation of cholinergic interneurons reveals their regulating role on the direct and indirect output pathways from the striatum. Neurobiology of Disease 2018, 109 , 148-162. https://doi.org/10.1016/j.nbd.2017.10.010
    76. Werend Boesmans, Marlene M. Hao, Pieter Vanden Berghe. Optogenetic and chemogenetic techniques for neurogastroenterology. Nature Reviews Gastroenterology & Hepatology 2018, 15 (1) , 21-38. https://doi.org/10.1038/nrgastro.2017.151
    77. Deniz Atasoy, Scott M. Sternson. Chemogenetic Tools for Causal Cellular and Neuronal Biology. Physiological Reviews 2018, 98 (1) , 391-418. https://doi.org/10.1152/physrev.00009.2017
    78. Patrick A. Forcelli. Applications of optogenetic and chemogenetic methods to seizure circuits: Where to go next?. Journal of Neuroscience Research 2017, 95 (12) , 2345-2356. https://doi.org/10.1002/jnr.24135
    79. Jingwei Jiang, Huxing Cui, Kamal Rahmouni. Optogenetics and pharmacogenetics: principles and applications. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 2017, 313 (6) , R633-R645. https://doi.org/10.1152/ajpregu.00091.2017
    80. Emily T. Stoneham, Daniel G. McHail, Katelyn N. Boggs, Sarah H. Albani, Jason A. Carty, Rebekah C. Evans, Kelly A. Hamilton, Victoria M. Saadat, Samanza Hussain, Maggie E. Greer, Theodore C. Dumas. Functional perturbation of forebrain principal neurons reveals differential effects in novel and well-learned tasks. Brain Research 2017, 1671 , 1-13. https://doi.org/10.1016/j.brainres.2017.06.024
    81. Juan L. Gomez, Jordi Bonaventura, Wojciech Lesniak, William B. Mathews, Polina Sysa-Shah, Lionel A. Rodriguez, Randall J. Ellis, Christopher T. Richie, Brandon K. Harvey, Robert F. Dannals, Martin G. Pomper, Antonello Bonci, Michael Michaelides. Chemogenetics revealed: DREADD occupancy and activation via converted clozapine. Science 2017, 357 (6350) , 503-507. https://doi.org/10.1126/science.aan2475
    Download PDF
    Go to ACS Chemical Neuroscience
    Get e-Alerts
    Get e-Alerts

    ACS Chemical Neuroscience

    Cite this: ACS Chem. Neurosci. 2017, 8, 7, 1570–1576
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acschemneuro.7b00079
    Published March 21, 2017
    Copyright © 2017 American Chemical Society
    Request reuse permissions

    Article Views

    3517

    Altmetric

    -

    Citations

    79
    Learn about these metrics

    Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.

    Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.

    The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.