Ketamine, used for treatment-resistant depression, shows reinforcing effects in both male and female rats at higher doses (0.25 and 0.5 mg/kg/infusion), with females self-administering more at the highest dose. All doses that supported self-administration led to cue-induced reinstatement. After reinstatement, ketamine-treated animals had higher cFos protein expression in the nucleus accumbens than saline controls, with greater expression in the core than shell subregion, and no sex differences in this neural activation. These dose- and sex-dependent effects highlight the need for further research into ketamine's addictive potential, especially at lower clinical doses.
Repeated ketamine infusions for depression may be riskier in people with a history of alcohol use, and effects differ by sex. In rats, females self-administered more ketamine than males. A history of alcohol increased ketamine intake in females, while a history of either isolation or alcohol independently increased ketamine intake in males. All groups showed similar extinction and cue-induced reinstatement. In the nucleus accumbens, isolation increased immature dendritic spines in males, an effect reduced by alcohol; alcohol increased immature spines in females. The findings suggest that prior social isolation and alcohol exposure alter ketamine's reinforcing properties in a sex-dependent manner, highlighting the need to consider sex and alcohol history when using ketamine to treat depression.