Stressed Avoider rats show blunted sensitivity to alcohol’s aversive effects: Potential contributions of the lateral habenula and lateral hypothalamus

Avoidance coping following stress exposure predicts heightened alcohol drinking. Similarly, blunted sensitivity to the aversive effects of alcohol facilitates increased drinking. However, the relationship between stress exposure, coping mechanism, and sensitivity to alcohol’s aversive effects is unknown. In rats, predator odor stress increases alcohol intake in animals that show persistent avoidance of stress-paired stimuli, termed “Avoiders”. Here, we tested the hypothesis that Avoider rats have blunted sensitivity to alcohol’s aversive effects using an alcohol-induced conditioned taste aversion (CTA) paradigm. After a single conditioning session, Non-Avoider rats acquired alcohol-induced CTA while Avoiders did not. Male rats across all groups eventually acquired alcohol CTA after four conditioning sessions. However, in females, only Non-Avoiders acquired alcohol-induced CTA. In male Non-Avoider rats, a single CTA-inducing dose of alcohol increased cFos expression in the lateral habenula (LHb), an important nucleus in aversion signaling. In male Avoiders, the same dose of alcohol decreased LHb cFos expression. cFos expression in the lateral hypothalamus (LH), which provides glutamatergic inputs to the LHb, was also diminished by alcohol in male Avoider rats. In females, alcohol had no effect on cFos cell counts in the LHb. However, in the LH, alcohol diminished cFos expression in female Non-Avoiders. Collectively, these findings suggest that stressed Avoider rats are hyposensitive to alcohol’s aversive effects, which may facilitate their heightened alcohol drinking after stress. Sex- and stress group-specific differences in LH and LHb recruitment highlight these regions as candidates for mediating stress-induced changes in alcohol behaviors.