Sex-associated differences in incentive salience and drinking behavior in a rodent model of alcohol relapse

Abstract The ability of environmental cues to trigger alcohol-seeking behaviors is thought to facilitate problematic alcohol use. The tendency to attribute incentive salience to cues varies between individuals and may constitute a risk factor for the development of addiction. Understanding the relationship between incentive salience and alcohol addiction may help inform prevention and treatment strategies for addiction. Animal studies have focused predominantly on males of alcohol-preferring strains of rodents. We sought to study the relationship between incentive salience and alcohol addiction using non-preferring rats to model the heterogeneity of human alcohol consumption, investigating both males and females. Here, adult RccHan Wistar rats were subjected to the alcohol deprivation effect (ADE) paradigm, mimicking alcohol relapse in humans. They were given voluntary access to different alcohol solutions in a four-bottle paradigm with repeated interruptions by deprivation and reintroduction phases over a protracted period (5 ADE cycles). Before each ADE cycle, rats were tested in the Pavlovian Conditioned Approach (PCA) paradigm, which quantifies the individual tendency toward a conditional cue and the reward, thus allowing us to trace the process of attributing incentive salience to reward cues. During the final ADE cycle (ADE5), animals were tested for compulsive-like behavior using quinine taste adulteration. Associations between longitudinal drinking patterns, PCA performance, and eventual compulsive-like behavior were analyzed. We investigated sex differences in drinking behavior and PCA performance; females drank significantly more alcohol than males throughout all ADE phases and displayed more sign-tracking (ST) behavior in the PCA, whereas males showed goal-tracking (GT) behavior. PCA phenotypes emerged at the first ADE cycle and remained stable over subsequent cycles. When looking at the correlation between alcohol drinking and PCA performance, high drinkers exhibited more ST behavior, and low drinkers exhibited more GT behavior; initial PCA phenotype was correlated with later alcohol consumption. Our findings indicate a more complex relationship between incentive salience and alcohol addiction than previously suggested and emphasize the importance of considering individual differences and both sexes in preclinical research.