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 (0.4 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.

Sex differences in the reduction of impulsive choice (delay discounting) for cocaine in rats with atomoxetine and progesterone

“…This disparity in the effect of ATO on sucrose pellets and cocaine suggests that it is interacting with some aspect of the impulsive choice for cocaine procedure. Indeed, recent work by Swavle et al (2016) showed males (vs. females) had a relatively greater reduction in cocaine-seeking behavior during reinstatement when treated with the same dose of ATO (1.5 mg/kg) used in the present study. Given the present results and the lack of studies examining sex differences in the effects of ATO on cocaine self-administration, additional research in this area is warranted.…”

“…The PRO dose was based on previous work that found it was effective in reducing cocaine and cue-primed reinstatement as well as reducing breakpoints for cocaine on a progressive ratio schedule (e.g., Larson et al 2007; Zlebnik et al 2014). The ATO dose was selected based on previous research showing it reduced cocaine seeking (Swavle et al 2016; Zlebnik and Carroll 2014) and impulsive choice at doses of 1–2 mg/kg (e.g., Bizot et al 2011; Robinson et al 2008). …”

“…However, ATO has other characteristics that make it a promising candidate. In animal models of drug abuse and relapse, ATO treatment alone (Economidou et al 2009; Economidou et al 2011) or in combination with other treatments reduced cue- and/or cocaine-primed cocaine seeking in male (Swalve et al 2016) and female (Zlebnik and Carroll 2014) rats, but did not reduce cocaine self-administration in humans (Economidou et al 2011; Levin et al 2009; Walsh et al 2013). Taken together, these studies suggest that ATO may be an effective treatment to reduce impulsive choice for cocaine for both sexes.…”

“…For example, the duel effects of wheel running, PRO and ATO when combined are typically more effective at reducing cocaine-seeking (see Swalve et al 2016; Zlebnik and Carroll 2014; Zlebnik et al 2014)) in male and female rats than when administered alone (see also, Comer et al 1996). Since ATO and PRO treatments are presumed to impact impulsive choice for cocaine differently, they were presumed to be more effective in combination.…”

Sex-specific attenuation of impulsive action by progesterone in a go/no-go task for cocaine in rats

“…Progesterone (PRO; Sigma Aldrich, St. Louis, MO) was dissolved in peanut oil (VEH; Sigma Aldrich) to a final dose of 0.5 mg/kg administered subcutaneously 30 minutes prior to experimental sessions. This dose has produced endogenously relevant levels of PRO (Jackson et al 2006), and it decreased cocaine-seeking and impulsivity for food and cocaine in our previous studies (see Anker et al 2011 for a review; Smethells et al 2016; Swalve et al 2016a, b, d; Zlebnik et al 2014). …”