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Allosteric Modulation of GABAA Receptors in Rat Basolateral Amygdala Blocks Stress-Enhanced Reacquisition of Nicotine Self-Administration

  • Burt M. Sharp*
    Burt M. Sharp
    Department of Genetics, Genomics and Informatics, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States
    *Email: [email protected]
  • Qin Jiang
    Qin Jiang
    Department of Genetics, Genomics and Informatics, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States
    More by Qin Jiang
  • Xenia Simeone
    Xenia Simeone
    Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Vienna, 1090, Austria
  • , and 
  • Petra Scholze
    Petra Scholze
    Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Vienna, 1090, Austria
Cite this: ACS Pharmacol. Transl. Sci. 2020, 3, 6, 1158–1164
Publication Date (Web):October 19, 2020
https://doi.org/10.1021/acsptsci.0c00111
Copyright © 2020 American Chemical Society

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    Abstract

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    Stress is a major determinant of relapse to smoked tobacco. In a rat model, repeated stress during abstinence from nicotine self-administration (SA) results in enhanced reacquisition of nicotine SA, which is dependent on the basolateral amygdala (BLA). We postulate that repeated stress during abstinence causes hyperexcitability of the BLA principal output neurons (PNs) due to disinhibition of the PNs from reduced inhibitory regulation by local GABAergic interneurons. To determine if enhanced GABAergic regulation of the BLA PNs can lessen the effects of stress on nicotine intake, positive allosteric modulators (PAMs) of GABAA receptors were infused into the BLA immediately prior to reacquisition of nicotine SA. Three selective PAMs [NS 16085 (binds the benzodiazepine site on α2/α3 GABAA); DCUK-OEt (binds a novel, benzodiazepine site on α1 or α5, β2 or β3, γ2 or δ GABAA); DS2 (binds exclusively to δ GABAA] with varied GABAA subunit specificities abolished the stress-induced amplification of nicotine taking during reacquisition. These studies indicate that highly selective PAMS targeting α3 or δ subunit-containing GABAA in the BLA may be effective in ameliorating the stress-induced relapse to smoked tobacco during abstinence from cigarettes.

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    Cited By

    This article is cited by 1 publications.

    1. Andrew M. Novick, Korrina A. Duffy, Rachel L. Johnson, Mary D. Sammel, Wen Cao, Andrew A. Strasser, Mehmet Sofuoglu, Alexandra Kuzma, James Loughead, A. Leslie Morrow, C. Neill Epperson. Effect of progesterone administration in male and female smokers on nicotine withdrawal and neural response to smoking cues: role of progesterone conversion to allopregnanolone. Biology of Sex Differences 2022, 13 (1) https://doi.org/10.1186/s13293-022-00472-w

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