Chronic Alcohol Drinking Drives Sex-Specific Differences in Affective Behavior and Medial Prefrontal Cortex Activity in CRF1:Cre:Tdtomato Transgenic Rats

Alcohol use disorders (AUDs) are characterized by compulsive alcohol use, loss of control over intake, and a negative emotional state during abstinence. While AUDs are associated with both mood and chronic pain disorders, the relationship between these associations remains unclear. Corticotropin releasing factor-1 receptor (CRF1) has been implicated in alcohol (EtOH) use, affective states, and pain sensitivity; often in a sex-dependent manner. Using CRF1-cre transgenic rats, we found no sex differences in basal affective behavior with the exception of mechanical sensitivity, where females were more sensitive to mechanical stimuli. Following baseline testing, rats began EtOH (or water) drinking under intermittent access conditions. Females consumed more alcohol in the first week, but overall EtOH intake was not significantly different between males and females. Following 3-4 weeks of drinking, rats were tested again for negative affect. EtOH drinking decreased mechanical sensitivity, but no other group effects were observed. However, individual EtOH intake was directly correlated with anxiety- and depressive-like behavior in both sexes. Interestingly, EtOH intake inversely correlated with thermal sensitivity in males only. There were no group differences in CRF1+ neuronal activity in either prelimbic or infralimbic cortices, but final session EtOH intake was significantly correlated with activity in CRF1+ neurons in the infralimbic cortex. Together, our results suggest complex interplay between affective state, EtOH drinking, and the role of prefrontal cortex CRF1-containing neurons in mediating these behaviors. Additionally, these results highlight the importance of examining individual differences in AUD-related behaviors.SIGNIFICANCE STATEMENTDespite alcohol use disorders being extremely comorbid with mood and pain disorders, there is still a limited understanding of the interaction and directionality between the them. To investigate this problem, rats were tested for affective behavior before and after being allowed to drink alcohol for 6 weeks. While baseline behavior did not predict subsequent intake, alcohol intake predicted both anxiety- and depressive-like behavior. These findings were accompanied by increased activity of the corticotropin releasing factor 1 containing neurons in the infralimbic region of the prefrontal cortex. Together, these findings reveal a new mechanism for understanding alcohol use.