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

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