Brunke, O. R. | bioRxiv Science

bioRxiv2025

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 alcohols 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 alcohols 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 alcohols 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. HighlightsO_LIAvoider rats exhibit blunted sensitivity to alcohols aversive effects C_LIO_LIAlcohol dose increases cFos expression in the lateral habenula of male Non-Avoiders C_LIO_LIAlcohol dose diminishes cFos expression in the LHb and LH of male Avoiders C_LI

neuroscience↗

bioRxiv2025

Predator odor stress produces sex- and subpopulation-specific increases in alcohol drinking, anxiety-like behavior, and lateral hypothalamic crh expression

Traumatic stress leads to maladaptive avoidance behaviors and alcohol misuse in some people. In rats, predator odor ("traumatic") stress produces persistent avoidance of stress-paired contexts and escalated alcohol self-administration in some animals (Avoiders), but not others (Non-Avoiders). This mirrors the individual differences in stress responsivity and alcohol misuse seen in humans. Here, we used a quinine-adulterated alcohol drinking procedure to model compulsive-like alcohol drinking in humans. Male and female Wistar rats were given 12 weeks of intermittent access to 20% (v/v) alcohol, followed by three weeks of limited access. Rats were then indexed for avoidance using predator odor stress exposure, and limited access drinking resumed for three additional weeks after stress. During this period, the alcohol solution was adulterated twice weekly with increasing concentrations of quinine. More Avoidant males were more resistant to quinine adulteration and Avoider males increased in non-quinine alcohol drinking. Using ultrasonic vocalizations (USVs) as a measure of affective state, we found that Non-Avoider males emitted more lower frequency USVs (<32 kHz) preceding, during, and following predator odor stress. Finally, quantification of crh, crhr1, crhr2, crhbp gene expression in the lateral hypothalamus revealed a strong positive correlation between greater crh transcripts and avoidance in males and a positive correlation between crh transcripts and less anxiety-like behaviors in females. Together, these results suggest that the intersection of stress and compulsive-like alcohol drinking is sex-specific and dependent on individual differences in stress outcomes. This work reinforces the importance of considering sex differences in stress and alcohol use disorder research. HighlightsO_LIMale Avoider rats show elevated two-bottle choice alcohol drinking after predator odor stress C_LIO_LIMore avoidant males show more aversion-resistant alcohol drinking C_LIO_LIFemale Avoider rats show heightened anxiety-like behavior 4 weeks after stress C_LIO_LILow frequency USVs predict Non-Avoider behavior in male rats C_LIO_LICrh expression in the LH is correlated with avoidance and alcohol drinking in male rats C_LI

neuroscience↗