Wistar rats choose alcohol over social interaction in a discrete-choice model

Animal models of substance use disorders (SUDs), while advancing our understanding of addiction neurobiology, have yielded limited clinical treatment breakthroughs. The failure of promising mechanisms identified in animal models, such as CRH1 receptor antagonism for alcohol use disorder (AUD), in clinical trials highlights the need for refined preclinical models. One critical factor often overlooked is the availability of alternative non-drug rewards. Addiction involves a progressive shift toward drug preference over healthy rewards like social interaction, supported by epidemiological links between poor social integration and drug use. Existing choice-based models typically use food or sweet solutions as alternatives to drugs. Our previous work showed that only about 15% of Wistar rats consistently choose alcohol over saccharin. Venniro et al. developed a model showing social interaction attenuated stimulant and opioid self-administration and craving. However, the generalizability of this social choice model to alcohol remains unknown. This study aimed to evaluate the choice between alcohol and social rewards in Wistar rats under various experimental conditions to determine if the social choice model generalizes to alcohol.

Existing literature highlights the limitations of current animal models of addiction in translating to human treatments. Studies have shown that alternative non-drug rewards can significantly influence drug seeking and taking behaviors. The importance of social factors in addiction is underscored by epidemiological studies showing a strong correlation between social isolation and drug use. While studies using choice-based models have shown that food or sweet solutions can reduce drug self-administration, fewer studies have investigated the role of social interaction. Previous research using a novel operant model demonstrated that social interaction prevents methamphetamine self-administration and craving. However, whether this also applies to alcohol remains an open question. This study aimed to bridge this gap.

The study used adult male and female Wistar rats (n=176 total, including 48 social partners). Experiments were conducted in accordance with Swedish animal ethics guidelines. The study comprised four experiments. Experiment 1 examined the effect of interaction duration and partner familiarity on alcohol vs. social interaction choice using 32 male rats trained to self-administer alcohol or social interaction (cagemate) under FR1 reinforcement. A discrete-trials choice procedure was used to assess preferences. Experiment 2 assessed the influence of short (2 hours) and chronic isolation on choice, using 32 test rats and 16 partners. Experiment 3 investigated whether social interaction functions as a reinforcer by training alcohol-naïve rats to self-administer social interaction under FR1 and FR2 schedules, varying housing conditions for both test and partner rats. Experiment 4 explored sex differences in motivation and choice by training 32 rats (16 male, 16 female) on an alternating self-administration procedure, followed by progressive ratio (PR) and discrete choice procedures. Data were analyzed using ANOVA and post-hoc tests. Detailed procedures, including training protocols, response requirements, and choice procedures are provided in the Supplementary Methods.

Experiment 1 showed that rats consistently preferred alcohol over social interaction with a cagemate, irrespective of interaction duration. Experiment 2 showed that while chronic isolation increased motivation for social interaction, it did not alter the preference for alcohol over social interaction. Rats continued to show high preference for alcohol even when the effort to obtain it was 10-16 times higher than that for the social reward. Experiment 3 demonstrated that social interaction functions as a reinforcer, particularly in chronically isolated rats paired with group-housed partners. However, even with increased social reinforcement, alcohol preference remained high. Experiment 4 revealed that males displayed higher motivation and self-administration for alcohol than females, but no sex differences were observed in social reward seeking or choice. Both sexes strongly preferred alcohol over social interaction, although females shifted towards social reward at higher effort levels for alcohol. Overall, the vast majority of rats (approximately 90%) consistently preferred alcohol over social interaction across various conditions.

The study's findings contradict previous research using social choice models with other drugs, which showed that social interaction reduced self-administration of stimulants and opioids. This discrepancy might stem from differences in drug administration routes (oral vs. intravenous), rat strains (Wistar vs. Sprague-Dawley), or the relative reinforcing value of social interaction compared to other alternative rewards like saccharin. The consistent preference for alcohol over social interaction, even with increased effort costs, suggests unique interactions between alcohol and social rewards. Previous studies showed that social factors can both positively and negatively influence alcohol use and relapse. The findings suggest alcohol's potent rewarding effects override the reinforcing value of social interaction in these experiments. The stronger reinforcing properties of alcohol, along with potential confounding factors like stress induced by isolation, may explain the observed strong preference for alcohol.

This study demonstrates that Wistar rats strongly prefer alcohol over social interaction in a discrete choice paradigm, a finding that contrasts with results using other drugs. This preference persists regardless of several experimental manipulations, highlighting potential unique interactions between alcohol and social reward. Future research should explore the underlying mechanisms driving this strong alcohol preference, investigate the role of different rat strains, and examine the relative reinforcing power of social interaction compared to other rewards. Further research is needed to fully understand the complex interplay between alcohol, social factors, and addiction.

The study primarily used Wistar rats, limiting the generalizability of the findings to other rat strains. The use of oral alcohol administration might influence the results compared to intravenous administration used in other studies. The experimental design, while comprehensive, might not encompass all factors influencing alcohol vs. social reward choice. The study could benefit from further investigation into the neural mechanisms underlying the observed preference and the specific interactions between alcohol and social rewards.