Alcohol preferring (P) rats as a model for examining sex differences in alcohol use disorder and its treatment.

RATIONALE: Despite epidemiological and clinical data indicating marked gender differences in alcohol use disorders (AUDs), few preclinical studies have examined sex differences in animal models of AUDs. OBJECTIVE: The purpose of this study was to first characterize sex differences in ethanol consumption and reinforcement in an alcohol preferring (P) rat model of alcoholism, then use this model to screen pharmacological treatments for sex-specific effects. METHODS: Ethanol consumption was first assessed in male and female P rats under a three-bottle free-choice procedure. Next, ethanol's reinforcing effects were assessed under a fixed-ratio 1 (FR1) schedule followed by a progressive-ratio (PR) schedule. Finally, the effects of two pharmacological treatments for AUDs, naltrexone (1mg/kg) and topiramate (10 or 20mg/kg), alone and in combination, were tested for sex-specific differences in their efficacy at reducing ethanol's reinforcing effects. RESULTS: Although females initially had higher consumption of and preference for ethanol, male rats increased their consumption and preference over time and rapidly became equal to females. Following prolonged 24-hour/day access, males and females self-administered similar levels of ethanol under FR1 and PR schedules. In response to pharmacological treatment, we observed some sex differences and similarities, most notably, a more robust effect of the combination of naltrexone and topiramate in males as compared to females. CONCLUSIONS: This model of selectively bred P rats may be useful for understanding sex differences in AUDs and related behavior and their underlying neurobiological mechanisms and treatment.