title: Sex differences in reinstatement of cocaine-seeking with combination treatments of progesterone and atomoxetine.
abstract: 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 (0.4mg/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 (0.5mg/kg) alone (PRO+SAL), ATO (1.5mg/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.
authors.affiliation: Department of Psychiatry, University of Minnesota, Minneapolis, MN, 55455, USA. Electronic address: nlswalve9220@gmail.com.
authors.forename: Natashia
authors.initials: N
authors.lastname: Swalve
authors.affiliation: Department of Psychiatry, University of Minnesota, Minneapolis, MN, 55455, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Smethells
authors.affiliation: Department of Psychiatry, University of Minnesota, Minneapolis, MN, 55455, USA.
authors.forename: Natalie E
authors.initials: NE
authors.lastname: Zlebnik
authors.affiliation: Department of Psychiatry, University of Minnesota, Minneapolis, MN, 55455, USA.
authors.forename: Marilyn E
authors.initials: ME
authors.lastname: Carroll
mesh_terms: D000818:Animals; D000069445:Atomoxetine Hydrochloride / Q000494:pharmacology* / Q000627:therapeutic use*; D002110:Caffeine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D003463:Cues; D004347:Drug Interactions; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D005108:Extinction, Psychological / Q000187:drug effects; D005260:Female; D008297:Male; D011374:Progesterone / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats; D012646:Self Administration; D012727:Sex Characteristics
chemical_list: D002110:Caffeine; D011374:Progesterone; D000069445:Atomoxetine Hydrochloride; D003042:Cocaine
keywords: Atomoxetine; Caffeine; Cocaine; Combination treatment; Progesterone; Reinstatement