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.