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

Burt M Sharp; Qin Jiang; Xenia Simeone; Petra Scholze

doi:10.1021/acsptsci.0c00111

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

ACS Pharmacol Transl Sci. 2020 Oct 19;3(6):1158-1164. doi: 10.1021/acsptsci.0c00111. eCollection 2020 Dec 11.

Authors

Burt M Sharp¹, Qin Jiang¹, Xenia Simeone², Petra Scholze²

Affiliations

¹ Department of Genetics, Genomics and Informatics, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States.
² Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Vienna, 1090, Austria.

Abstract

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 GABA_A 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 GABA_A); DCUK-OEt (binds a novel, benzodiazepine site on α1 or α5, β2 or β3, γ2 or δ GABA_A); DS2 (binds exclusively to δ GABA_A] with varied GABA_A 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 GABA_A in the BLA may be effective in ameliorating the stress-induced relapse to smoked tobacco during abstinence from cigarettes.