Age- and sex-driven alterations in alcohol consumption patterns: Role of brain ethanol metabolism and the opioidergic system in the nucleus accumbens

Abstract

Alcohol consumption leads to significant neurochemical and neurobiological changes, contributing to the development of alcohol use disorders (AUDs), which exhibit sex- and age-dependent variations according to clinical data. However, preclinical studies often neglect these factors when investigating alcohol consumption patterns. In this study, we present data on male and female rats continuously exposed to a 20 % ethanol solution for one month. The animals were divided into two groups based on their age at the onset of drinking (8 and 12 weeks old). Interestingly, 12-week-old males consumed significantly less alcohol than both 12-week-old females and 8-week-old animals, indicating that alcohol consumption patterns vary with sex and age in our model. Additionally, to advance in the study of the neurobiological alterations induced by ethanol intake in the mesocorticolimbic system (MCLS) that may participate in its reinforcing properties and the maintenance of alcohol drinking behavior, we measured catalase activity—an enzyme involved in alcohol metabolism and related to ethanol reinforcement—in the nucleus accumbens (NAc) of these animals. Furthermore, we measured the levels of mu (MOR), kappa (KOR), delta (DOR), and nociceptin (NOP) opioid receptors in the NAc, as the endogenous opioidergic system plays a pivotal role in regulating the MCLS and alcohol reinforcement. MOR levels were lower in high alcohol-consuming groups (8-week-old males and all females). Both DOR and NOP levels decreased with age, whereas KOR levels remained unchanged. Our findings suggest that the age at onset of alcohol consumption critically influences alcohol intake, particularly in males. Additionally, females consistently showed higher alcohol intake regardless of age, highlighting inherent sex-specific differences. The dynamic changes in catalase activity and opioid receptor expression suggest the involvement of these factors in modulating alcohol consumption.