A rat model of addiction and withdrawal syndrome and the effect of D2/5-HT3 receptor modulation

Alcohol addiction and related behavioral disorders remain a significant global public health challenge, with withdrawal syndrome representing a major obstacle to long-term recovery and a primary cause of treatment failure and relapse. The physical and psychological distress experienced during abstinence often forces individuals to return to drinking, creating a cycle that is difficult to break with current therapeutic options. Chronic alcohol consumption disrupts key neurotransmitter systems involved in reward and stress regulation, contributing to craving and the persistence of addictive behavior. Pharmacological approaches therefore aim not only to manage withdrawal symptoms but also to restore balance within these dysregulated neural circuits. This includes reducing excessive reward signaling, as well as more nuanced modulation of receptor activity to stabilize neurotransmission. In addition, targeting other systems related to stress and conditioned responses may further support abstinence. Overall, this reflects a shift toward more integrated treatment strategies that address the complex neurobiological basis of alcohol dependence.

This project aims to develop and validate a robust model of alcohol dependence and withdrawal symptoms in rats, focusing on the behavioral manifestations of this syndrome and the neurobiological mechanisms that lead to relapse. Adult male and female rats are administered alcohol under a controlled experimental protocol designed to reliably induce physiological dependence while maintaining translational relevance to human consumption patterns. This method is based on the periodic administration of a solution with increasing alcohol concentrations by the experimenter, alongside gradually increasing voluntary intake by the rats. During and after alcohol exposure, addiction- and withdrawal-related behaviors are comprehensively assessed using a set of validated tests sensitive to changes in locomotor activity, anxiety-like states, and depression-like markers. These include the open-field test to quantify hyperactivity or deficits in exploratory behavior, direct social interaction to assess changes in social behavior, and the elevated plus maze and light–dark box tests to evaluate anxiety-like behavior during withdrawal. A central component of the study is the modeling of relapse-like behavior through repeated alcohol exposure and stress-induced reinstatement, which allows for the measurement of alcohol-seeking intensity.

Due to the need for more effective therapeutic approaches, we are investigating the pharmacological modulation of dopaminergic and serotonergic systems, which play a significant role in reward processing and motivation. Specifically, we focus on dopamine and serotonin receptor modulation by known drugs (Aripiprazole, Cariprazine, Risperidone, and Ondansetron) and candidate molecules that bind to the D2 receptor and the serotonin 5-HT3 receptor. We hypothesize that dual-acting substances, functioning simultaneously as 5-HT3 receptor antagonists and D2 receptor modulators, will be more effective than existing therapies in suppressing alcohol craving and managing withdrawal distress. By combining these behavioral assessments with targeted receptor modulation, this study provides a detailed overview of the temporal dynamics of withdrawal symptoms and identifies new therapeutic strategies. These results are expected to confirm the validity of our experimental model as a predictive tool for preclinical testing of drugs targeting addiction and withdrawal syndrome.

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