Different mechanisms underlie compulsive alcohol self-administration in male and female rats

Sex is an important factor in the progression and treatment of alcohol addiction, and therapeutic approaches may have to be tailored to potential sex differences. This highlights the importance of understanding sex differences in behaviors that reflect key elements of clinical alcohol addiction, such as continued use despite negative consequences (“compulsive use”). Studies in experimental animals can help provide an understanding of the role sex plays to influence these behaviors. Large populations of genetically heterogeneous male and female Wistar rats were tested in an established model of compulsive alcohol self-administration, operationalized as alcohol responding despite contingent foot shock punishment. We also tested baseline (fixed ratio, unpunished) operant alcohol self-administration, motivation to self-administer alcohol (progressive ratio), and temporal discounting for alcohol reward. In search of predictors of compulsivity, animals were screened for novelty-induced place preference, anxiety-like behavior, pain sensitivity and corticosterone levels. The estrous cycle was monitored throughout the study. Unpunished self-administration of alcohol did not differ between males and females when alcohol intake was corrected for body weight. Overall, females showed higher levels of compulsive responding for alcohol. Compulsive response rates showed bimodal distributions in male but not in female rats when intermediate shock intensities were used (0.2 and 0.25 mA); at higher shock intensities, responding was uniformly suppressed in both males and females. We also found less steep discounting in females when alcohol was devalued by delaying its delivery. Males exhibited a stronger motivation to obtain alcohol under unpunished conditions, while females showed higher corticosterone levels at baseline. Factor analysis showed that an underlying dimension related to stress and pain predicted compulsivity in females, while compulsivity in males was predicted by a reward factor. We did not find differences in alcohol-related behaviors throughout the various stages of the estrous cycle. Our results suggest that mechanisms promoting compulsivity, a key feature of alcohol addiction, likely differ between males and females. This underscores the importance of considering sex as a biological variable in both preclinical and clinical research, and has potential treatment implications in alcohol addiction. Sex plays an important role in the progression and treatment of alcohol addiction. While men show a higher prevalence of alcohol addiction, women are more susceptible to the adverse effects of excessive alcohol consumption. Additionally, women often rely on heavy drinking as a maladaptive coping mechanism to alleviate stress and anxiety, driven by negative affect. On the other hand, men are more likely to report heavy drinking and relapse in response to positive emotions and social influences. These sex-based differences underline the importance of understanding how vulnerability to alcohol addiction and its treatment varies in males and females. We used genetically heterogeneous rats to explore the behavioral traits that contribute to compulsivity, a key clinical feature of alcohol addiction. We found that motivation to self-administer alcohol was higher in males, while females showed higher compulsive alcohol self-administration. In males, motivation to self-administer alcohol showed a significant correlation with compulsivity, while in females compulsivity was predicted by higher basal corticosterone levels. These findings underlie the importance of sex-specific factors in compulsive alcohol self-administration, with potential prevention and treatment implications in alcohol addiction.