Alcohol use disorders (AUDs) are a major problem across the United States. While AUD remains a complex human condition, it is difficult to isolate the directionality of anxiety and ethanol (EtOH) drinking from outside influences. The present study sought to investigate the relationship between affective states and EtOH intake using male and female Sprague Dawley rats. Using complementary tests of anxiety-and depressive-like behavior, we found sex-and test-specific differences in basal affective behavior such that females displayed enhanced anxiety-like behavior in the Splash Test and males displayed enhanced anxiety-like behavior in the Novelty Suppressed Feeding Test. Although there were no sex differences in EtOH intake and no correlation between anxiety-like behavior and subsequent EtOH intake, we did find that depressive-like behavior predicted future EtOH intake in females rats only. In addition, we observed an increase in depressive-like behavior is male rats in both the water and EtOH drinking groups. Furthermore, anxiety-like behavior, but not depressive-like behavior predicted subsequent EtOH intake in female rats. Lastly, we found a history of EtOH intake decreased pain thresholds in male and female rats. Together, these experiments provide important information on the complex interaction between negative affect and alcohol intake and how these two contexts reciprocally do, or do not, influence each other in a sex-specific manner.

Alcohol use disorders are complex conditions characterized in part by excessive ethanol (EtOH) drinking and withdrawal-induced malaise. The corticotropin releasing factor-1 receptor (CRF1) has been implicated in EtOH drinking, affective states, and pain sensitivity; often in a sex-dependent manner. The studies presented here investigate the associations between baseline behavior, chronic intermittent EtOH intake, and withdrawal-induced affective behavior in male and female CRF1:cre:tdTomato rats. There were no sex differences in basal affective state or thermal sensitivity, as measured by the splash test, novelty suppressed feeding test, and Hargreaves, respectively. However, female rats displayed increased mechanical sensitivity, measured by the Von Frey test. Following baseline testing, rats underwent voluntary EtOH or water drinking under intermittent access conditions. Female rats consumed significantly more EtOH, but only during the first week. There were no group effects of EtOH on behavioral tests, but all of the rats demonstrated increased malaise upon repeated testing. There were significant individual differences where affective behavior positively correlated with negative affect in both sexes. There were also significant correlations between EtOH intake and CRF1-cFos co-expression in the infralimbic cortex and basolateral amygdala. EtOH decreased CRF1+ expression in the lateral amygdala, but there were no significant group effects of EtOH on cFos or CRF1-cFos co-expression in the medial prefrontal cortex or amygdala. Together, these results illustrate the complex interplay between affect, pain sensitivity, EtOH drinking, and the role of CRF1 containing neurons in mediating these behaviors.

In 2021, 131 million adult Americans reported drinking alcohol in the last month, despite the well-known consequences of alcohol consumption. While alcohol use disorders are associated with both mood and chronic pain disorders, the relationship between alcohol drinking and affective and nociceptive behaviors remains unclear. Corticotropin releasing factor receptor-1 (CRF1) has been implicated in alcohol drinking, affective states, and pain sensitivity; often in a sex-dependent manner. In order to probe the effects of alcohol drinking on activity of CRF1+ cells and to also test the hypothesis that alcohol drinking is associated with both basal and subsequent affective and nociceptive readouts, we put male and female CRF1:cre:tdTomato rats through a battery of behavioral tests before and after intermittent access to alcohol. Following baseline testing, rats began alcohol (or water) drinking. Females consumed more alcohol in the first week, but there was no effect of sex on overall alcohol intake. Following 3-4 weeks of drinking, behavioral tests were repeated. Alcohol drinking decreased mechanical sensitivity, but no other effects of alcohol drinking were observed between experimental groups. Individual alcohol intake correlated with affective behavior in both sexes but only correlated with thermal sensitivity in males. There were no main effects of alcohol drinking or sex on CRF1+ neuronal activity in the medial prefrontal cortex but final session alcohol intake correlated with activity in CRF1+ neurons in the infralimbic subregion. Together, our results suggest complex interplay between affective state, alcohol drinking, and the role of prefrontal CRF1+ neurons in mediating these behaviors.SIGNIFICANCE STATEMENTDespite alcohol use 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 subsequent affective behavior on an individual subject basis. 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.