Sex differences in reinstatement of cocaine-seeking with combination treatments of progesterone and atomoxetine

• Female rats self-administered more cocaine than males.
• Female rats were more sensitive to caffeine reinstatement than males.
• Individual treatment with progesterone decreased reinstatement in females.
• The combination of progesterone and atomoxetine decreased reinstatement.
• Male and female rats differentially responded to combination treatments.

Two repurposed medications have been proposed to treat cocaine abuse. Progesterone, a gonadal hormone, and atomoxetine, a medication commonly used to treat attention deficit/hyperactivity disorder, have both been separately shown to reduce cocaine self-administration and reinstatement (i.e., relapse). The goal of the present study was to examine sex differences in the individual effects of PRO and ATO as well as the combination PRO + ATO treatment on cocaine (COC), caffeine (CAF), and/or cue-primed reinstatement of cocaine-seeking. Adult male and female Wistar rats lever-pressed under a FR 1 schedule for cocaine infusions (0.4 mg/kg/inf). After 14 sessions of stable responding in daily 2-h sessions, rats underwent a 21-day extinction period when no drug or drug-related stimuli were present. Rats were then separated into four groups that received PRO (0.5 mg/kg) alone (PRO + SAL), ATO (1.5 mg/kg) alone (VEH + ATO), control (VEH + SAL) or combination (PRO + ATO) treatments prior to the reinstatement condition. Reinstatement of cocaine-seeking to cues and/or drug injections of cocaine or caffeine was tested after extinction. During maintenance, females self-administered more cocaine than males, but no sex differences were seen during extinction. Females showed greater cocaine-seeking than males after a CAF priming injection. Individual treatment with ATO did not decrease reinstatement under any priming condition; however, the combination treatment decreased cocaine-seeking under the COC + CUES priming condition in males, and both PRO alone and the combination treatment decreased cocaine-seeking in the CAF + CUES condition in females. Overall, PRO alone was only effective in reducing reinstatement in females, while the combination treatment was consistently effective in reducing reinstatement in both sexes.