Sex differences in reinstatement of cocaine-seeking with combination treatments of progesterone and atomoxetine - PubMed (original) (raw)

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

Natashia Swalve et al. Pharmacol Biochem Behav. 2016 Jun.

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.

Keywords: Atomoxetine; Caffeine; Cocaine; Combination treatment; Progesterone; Reinstatement.

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Figures

Figure 1

Mean (±SEM) cocaine (0.4 mg/kg, IV) infusions over 10 sessions of the maintenance period (2 h daily sessions). The vertical bar with an asterisk indicates a difference between males (n=43) and females (n=45) on total infusions during the 10 sessions of maintenance. Data from some animals on the first 5 sessions of maintenance has been previously published (Swalve et al, 2015) * = p < 0.05.

Figure 2

Mean (±SEM) lever presses over the 21 sessions of extinction. The horizontal bar with an asterisk indicates a significant decrease in responding over 21 sessions of extinction in both males (n=43) and females (n=45). * = p < 0.05.

Figure 3

Mean (±SEM) active lever presses during reinstatement conditions in males and females * = p < 0.05. The saline days were averaged for display, as they were not significantly different. The bar with an asterisk represents differences in responding after all reinstatement conditions in males and females compared to the saline conditions.

Figure 4

Mean (±SEM) lever presses during a) CUES reinstatement session compared to b) COC and c) COC+CUES sessions. The bar with an asterisk represents differences in responding during the COC+CUES reinstatement session. Sample sizes for the VEH+SAL, VEH+ATO, PRO+SAL and PRO+ATO groups were 11, 11, 12, and 11 for females and 12, 10, 11, and 10 for males, respectively. * = p < 0.05.

Figure 5

Mean (±SEM) lever presses during the a) CAF and b) CAF+CUES reinstatement session. The bars with an asterisk show a significant difference in responding during the CAF reinstatement session between males and females and a difference between treatment groups during the CAF+CUES reinstatement session. Sample sizes for the VEH+SAL, VEH+ATO, PRO+SAL and PRO+ATO groups were 11, 11, 12, and 11 for females and 12, 10, 11, and 10 for males, respectively. * = p < 0.05.

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Sex differences in reinstatement of cocaine-seeking with combination treatments of progesterone and atomoxetine - PubMed (original) (raw)