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

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Alcohol; Compulsivity; Motivation; Operant self-administration; Sex differences; Stress.

Fig. 1

Experimental timeline

Fig. 2

Male and female rats do not differ in alcohol self-administration when corrected for body weight, but males show a higher motivation to self-administer alcohol. A Mean reinforcers (± SEM) and B mean of alcohol (g/kg) (± SEM) earned during a 30-min alcohol 20% FR2 self-administration). C Mean break points (± SEM) reached during a progressive ratio session of 11% alcohol in male and female rats. **p < 0.01, ***p < 0.001

Fig. 3

Female rats show a higher resistance to shock-punished alcohol self-administration at progressively increasing shock intensities. A Mean reinforcers, B resistance score, C dose intake (± SEM) earned during 30-min punished self-administration sessions of 20% EtOH (FR2). D–F Resistance score distribution of punished alcohol self-administration across 10 days color coded for males (blue) and females (red) under increasing shock intensities (0.2, 0.25 and 0.3 mA). ^##p < 0.01, ^###p < 0.001, **p < 0.01

Fig. 4

Female rats show a higher resistance to quinine-induced alcohol adulteration. A Resistance score (± SEM) obtained during 30-min quinine-adulterated alcohol self-administration (10, 100, 250 mg/l). B Preference score for quinine-adulterated water. ^###p < 0.001, **p < 0.01, ***p < 0.001

Fig. 5

Female rats show less steep temporal discounting of alcohol rewards. A, B Fitted hyperbolic of mean reinforcers (± SEM) in 30-min delayed alcohol self-administration and C discounting constant for males and females **p < 0.01

Fig. 6

Compulsivity is correlated with motivation for alcohol in males and with corticosterone levels in females. A Factor loadings according to each factor. B, C, D Correlation analysis between activity of Factor 1, 2 and 3 generated through the factor analysis (see Results for definition) and resistance score. E Correlation table for individual primary variables for males (blue) and females (pink). F, G Correlational analysis between the resistance score, motivation and corticosterone levels in male and female rats, respectively. Values in two entry table are Pearson’s correlation values and p values (italic, below). Bold values are p values lower than 0.05. OA, open arms; BL, baseline