Sex- and age-specific effects on the development of addiction and compulsive-like drinking in rats

Background Biological factors are known to influence disease trajectories and treatment effectiveness in alcohol addiction and preclinical and clinical evidence suggests that sex is an important factor influencing disease dynamics in alcohol dependence. Another critical factor is age at first intoxicating drink, which has been identified as a risk factor for later alcohol binging. Preclinical research allows prospective monitoring of rodents throughout the lifespan, providing very detailed information that cannot be acquired in humans. Lifetime monitoring in rodents can be conducted under highly controlled conditions, during which one can systematically introduce multiple biological and environmental factors that impact behaviors of interest. Methods Here, we used the alcohol deprivation effect (ADE) rat model of alcohol addiction in a computerized drinkometer system, acquiring high-resolution data to study changes over the course of addictive behavior as well as compulsive-like drinking in cohorts of adolescent vs. adult as well as male vs. female rats. Results Female rats drank more alcohol than male rats during the whole experiment, drinking much more weak alcohol (5%) and similar amounts of stronger alcohol solutions (10%, 20%); female rats also consumed more alcohol than male rats during quinine taste adulteration. Increased consumption in females compared to males was driven by larger access sizes of alcohol. Differences in circadian patterns of movement were observed between groups. Early age of onset of drinking (postnatal day 40) in male rats had surprisingly little impact on the development of drinking behavior and compulsivity (quinine taste adulteration) when compared to rats that started drinking during early adulthood (postnatal day 72). Conclusions Our results suggest that there are sex-specific drinking patterns, not only in terms of total amount consumed, but specifically in terms of solution preference and access size. These findings provide a better understanding of sex and age factors involved in the development of drinking behavior, and can inform the preclinical development of models of addiction, drug development and exploration of options for new treatments. Highlights female rats show more pronounced compulsive-like behavior in response to quinine taste adulteration female rats consumed more alcohol than rats throughout the longitudinal experiment (similar to 11 months), driven by differences in access size and frequency of accesses adolescent and adult male rats did not differ in terms of drinking behavior and compulsive-like drinking sex differences in locomotor activity and circadian patterns were observed, with female rats moving more and having later peak activity in the day Plain language summary Various factors can influence the development of alcohol addiction, but studying these factors in humans over the long-term is challenging and costly. With modern sensing technologies, rodents can be monitored throughout the lifespan, providing detailed information obtained under controlled conditions. Previous research suggests sex- and age- dependent differences in addiction processes, with female rats consuming more alcohol and age at first drink resulting in heavier later consumption, but a better characterization of these is needed. Using a rodent model of addiction and relapse, collecting high-resolution longitudinal drinking data in a computerized system over 11 months, we studied differences in the development of addiction and compulsive-like drinking in male vs female as well as adult vs adolescent rats. Female rats drank more alcohol than male rats during the whole experiment, drinking much more weaker alcohol (5%) and similar amounts of stronger alcohol solutions (10%, 20%); female rats also consumed more alcohol than male rats in an aversive taste challenge, displaying more compulsive-like drinking. Increased consumption in females compared to males was driven by larger amounts consumed per approach. Little effect of age of onset of drinking was observed. Our results suggest sex-specific differences in the development of drinking patterns and solution preference, not only in terms of total amount consumed. These findings highlight the importance of awareness of sex-specific factors when developing models of addiction, as well as eventual treatment strategies and interventions.

Automated summary

Biological factors, such as sex and age, have a significant impact on the development of alcohol addiction. Preclinical research using rodent models allows for detailed monitoring of behaviors over the lifespan. In this study, female rats consumed more alcohol than male rats, especially weaker alcohol solutions. Differences in access size and frequency drove increased consumption in females. The findings highlight the importance of considering sex-specific factors in understanding addiction development and developing effective treatment strategies.