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

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. (C) 2016 Elsevier Inc. All rights reserved.