The bed nucleus of the stria terminalis regulates ethanol-seeking behavior in mice

Drug-associated stimuli are considered important factors in relapse to drug use. In the absence of drug, these cues can trigger drug craving and drive subsequent drug seeking. One structure that has been implicated in this process is the bed nucleus of the stria terminalis (BNST), a chief component of the extended amygdala. Previous studies have established a role for the BNST in cue-induced cocaine seeking. However, it is unclear if the BNST underlies cue-induced seeking of other abused drugs such as ethanol. In the present set of experiments, BNST involvement in ethanol-seeking behavior was assessed in male DBA/2J mice using the conditioned place preference procedure (CPP). The BNST was inhibited during CPP expression using electrolytic lesions (Experiment 1), co-infusion of GABAA and GABAB receptor agonists muscimol and baclofen (M+B; Experiment 2), and activation of inhibitory designer receptors exclusively activated by designer drugs (hM4Di-DREADD) with clozapine-N-oxide (CNO; Experiment 3). The magnitude of ethanol CPP was reduced significantly by each of these techniques. Notably, infusion of M+B (Exp. 2) abolished CPP altogether. Follow-up studies to Exp. 3 showed that ethanol cue-induced c-Fos immunoreactivity in the BNST was reduced by hM4Di activation (Experiment 4) and in the absence of hM4Di, CNO did not affect ethanol CPP (Experiment 5). Combined, these findings demonstrate that the BNST is involved in the modulation of cue-induced ethanol-seeking behavior.