Therapeutic Effects of Metformin on Cocaine Conditioned Place Preference and Locomotion

Lack of Food and Drug Administration-approved treatments for cocaine use disorder contributes to high rates of treatment attrition, relapse, and overdose. Metformin is a Type 2 diabetes drug being investigated for multiple new therapeutic indications. This study set out to determine whether metformin would impact the conditioned rewarding effects of cocaine in an abbreviated or standard two-chamber conditioned place preference (CPP) assay. Adult male (n = 73) and female (n = 82) Sprague Dawley rats were conditioned in a 7-day (abbreviated: 2 x 30 min sessions daily) or a 12-day timeline (standard: 1 x 30 min sessions daily) alternating control and treatment sessions using an unbiased design. Metformin (175 mg/kg) or saline pretreatment occurred 30 min before conditioning with cocaine (20 mg/kg) or vehicle (saline). Data showed sex differences in physiological responses to cocaine and metformin, as well as variant behavioral patterns with different conditioning paradigms. Metformin pretreatment impaired acquisition of cocaine CPP in abbreviated, but not standard conditioning among male rats only. Cocaine-induced locomotor effects are moderated with metformin pretreatment in both female and male rats in different phases of conditioning, suggesting the potential therapeutic value of symptom alleviation when tapering patients off cocaine use with the goal of abstinence. Sex differences observed highlight the importance in better understanding the unique pharmacological profiles of female and male patients. This study provides evidence supporting the potential repurposing of metformin for disrupting rewarding and psychomotor effects of cocaine, paving the way for safe, low-cost, and accessible treatment.