Allosteric modulation of GABAA receptors in rat basolateral amygdala blocks stress-enhanced reacquisition of nicotine self-administration

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 BLA principal output neurons (PN) due to disinhibition of PN from reduced inhibitory regulation by local GABAergic interneurons. To determine if enhanced GABAergic regulation of 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 (e.g., NS 16085, DCUK-OEt, DS2) with varied GABAA subunit specificities abolished the stress-induced amplification of nicotine taking during reacquisition. These studies indicate that highly selective PAMS targeting 3 or {delta} subunit-containing GABAA in BLA may be effective in ameliorating the stress-induced relapse to smoked tobacco during abstinence from cigarettes.