Simultaneous cocaine and ethanol self-administration promotes a sex-dimorphic pattern in drug-seeking behaviour and alters plasma amino acid profile related to glutamate homeostasis in young adult rats.

The concurrent use of cocaine and alcohol is highly prevalent in Western countries and carries a substantial risk of relapse in recovering process. Craving, characterized as a strong desire for consuming drugs, is a core feature of cocaine and ethanol use disorders and presents a significant challenge to maintaining abstinence and preventing relapse. The primary objective of this study was to explore the behavioural patterns associated with the incubation of drug-seeking for a cocaine-ethanol combination and, secondarily, to examine the plasma amino acid profile that might be associated with this combination. To achieve this, we employed an extended-access intravenous self-administration model over 10 sessions with both substances, followed by withdrawal periods of 2 and 30 days in young adult rats in both sexes. After the subsequent drug-seeking test, changes in plasma amino acid concentrations were examined. Cocaine and ethanol co-administration resulted in a lower consumption rate among rats compared to those consuming cocaine alone. However, both groups exhibited incubation of drug-seeking behaviour. Sex differences were observed in self-administration patterns and in the incubation of drug-seeking behaviour. Notably, after 30 days of withdrawal, alterations were detected in plasma levels of several amino acids, including glutamine, glycine, serine, threonine, and glutamate, which are associated with glutamate homeostasis. This study aims to contribute to our understanding of potential changes in the plasma amino acid profile in cocaine users who also consume ethanol, particularly during abstinence and craving incubation.