Effects of chronic social isolation stress and alcohol on the reinforcing properties of ketamine in male and female rats.

Abstract

While ketamine, an NMDA receptor antagonist, is effective in treating major depression, studies have not addressed the safety of repeated ketamine infusions in depressed patients with comorbid Alcohol Use Disorder (AUD). In this study, we aimed to determine whether a history of chronic social isolation and alcohol exposure alter the reinforcing properties of ketamine in male and female rats. Rats were pair-housed or socially isolated for 12 weeks and underwent intermittent access to 20% alcohol. Subsequently, rats underwent intravenous ketamine self-administration under a fixed ratio 1 schedule, followed by extinction training and one session of cue-induced reinstatement. Dendritic spine morphology was examined in the nucleus accumbens, an important area implicated in reward and motivation. Our results show that females self-administered more ketamine than males, a history of alcohol increased ketamine intake in females, and a history of isolation or alcohol independently increased ketamine intake in males. All experimental groups showed similar extinction patterns and reinstatement to ketamine cues. A pattern emerged similar to ketamine self-administration behaviors, where isolation increased the number of immature spines in males, a change that was attenuated in isolated alcohol drinkers, and a history of alcohol increased the number of immature spines in females. Our results suggest that a history of isolation and alcohol modulate the reinforcing properties of ketamine in a sex-dependent manner. This underscores the importance of considering sex differences and a history of alcohol use when employing ketamine to treat various psychopathologies, including major depression.Significance Statement Repeated infusions of ketamine, an NMDAR antagonist, show sustained reductions in major depressive disorder (MDD). Given the high comorbidity between MDD and Alcohol Use Disorder (AUD), we investigated the effects of a history of social isolation and alcohol on responding for ketamine. We showed sex differences in the effects of isolation stress and alcohol on ketamine intake alongside alterations in dendritic spine morphology in the nucleus accumbens. Overall, a history of alcohol consumption enhanced responding for ketamine. If extrapolated clinically, our research implies that adjustments in ketamine therapy should be made for individuals with a history of alcohol drinking undergoing treatment for MDD. Additionally, when formulating treatment protocols for this population, it is important to consider potential sex differences.