Effects of progesterone on escalation of intravenous cocaine self-administration in rats selectively bred for high or low saccharin intake

Abstract

Progesterone decreases cocaine self-administration in women and in female rats. In a previous study using rats selectively bred for high (HiS) and low (LoS) saccharin intake, HiS rats escalated their cocaine intake compared to LoS rats. Our goal was to examine the effects of progesterone on the escalation of cocaine self-administration in HiS and LoS rats. Four groups of female rats were compared: HiS P (progesterone-treated), LoS P, HiS VEH (vehicle-treated), and LoS VEH. Rats were trained to self-administer 0.8 mg/kg cocaine i.v. under a fixed-ratio 1 (FR 1) schedule during daily short-access (ShA) 2-h sessions. Rats then self-administered 3 randomly-presented doses of cocaine (0.2, 0.4, 1.6 mg/kg) and then had daily 6-h long-access (LgA) sessions with 0.4 mg/kg cocaine for 21 days. Cocaine intake was then reassessed with the 4 doses under the ShA condition. Throughout the experiment, rats were treated with daily s.c. injections of P (0.5 mg/kg) or an equal volume of VEH 30 min prior to each session. During the initial ShA condition, HiS rats earned more cocaine infusions than LoS rats at all doses, and during the subsequent LgA condition, HiS rats escalated cocaine intake, while the LoS rats maintained a steady rate. Progesterone treatment potentiated escalation of cocaine intake in the HiS rats but had an opposite effect on LoS rats, attenuating their cocaine self-administration. Results from the post-LgA dose-response ShA condition, indicated that both LoS and HiS VEH and P-treated rats earned more infusions than pre-LgA, but mainly at low doses. These results suggest that genetic differences in drug abuse vulnerability contribute differentially to treatment outcomes during escalation, a critical phase of the drug abuse process.

Cocaine-, caffeine-, and stress-evoked cocaine reinstatement in high vs. low impulsive rats: Treatment with allopregnanolone

“…The result that ALLO attenuated reinstatement more in LoI rats than HiI rats was consistent with recent studies involving phenotypes, such as high (HiS) vs. low (LoS) saccharin-preferring rats that were treated with progesterone (Anker et al, 2012) or baclofen (Holtz and Carroll, 2011) during long-access to cocaine self-administration. There was a more marked effect of progesterone and baclofen in LoS than HiS rats compared to their vehicle controls.…”

“…In previous studies of individual differences in drug seeking, results demonstrated differential responding to the positive and negative aspects of drug taking in HiS and LoS rats. While HiS rats exceeded LoS rats in drug intake (Perry et al, 2006, Anker et al, 2012) and reinstatement of drug-seeking behavior (Perry et al, 2006), LoS rats (vs. HiS) revealed greater reactivity to negative events, such as food restriction (Carroll et al, 2012) and withdrawal from ethanol (Dess et al, 2005), glucose (Yakavenko et al, 2011) morphine (Holtz et al, 2014b), and cocaine (Radke et al, 2014). Given the previous finding that lower drug-seeking animals respond more to negative aspects of drugs compared to higher drug-seeking animals, one potential explanation for the results that ALLO reduced reinstatement more in LoI than HiI rats is that these pharmacological manipulations produced more of a stress response in LoI rats compared to HiI rats.…”

“…To date, there have been very few preclinical animal studies that have addressed negative aspects of drugs of abuse in terms of the development and treatment of drug abuse, and there are even fewer studies in humans (Anker and Carroll, 2012; Carroll and Holtz, 2014; Holtz et al, 2013; Holtz and Carroll, 2011, 2014). In terms of prevention, it is particularly important to know how positive vs. negative aspects of drugs will affect relapse in groups that differentially administer drugs.…”

“…However, in recent studies of rats selectively bred for high or low saccharin intake (HiS vs. LoS), an opposite effect occurred. The lower self-administering LoS rats reduced their rate of escalation of cocaine intake, while their higher self-administering HiS counterparts increased their cocaine escalation when treated with progesterone (Anker et al, 2012) or baclofen (Holtz and Carroll, 2011). Thus, initial evidence suggests that phenotypic differences in self-administration might determine the success of interventions aimed to reduce drug seeking.…”

Effects of combined exercise and progesterone treatments on cocaine seeking in male and female rats

“…In women, high endogenous levels of P were associated with lower cue- and stress-induced cocaine craving (Sinha et al 2007). Animal models of the human drug abuse process also demonstrate P-mediated attenuation of cocaine-maintained behavior (Anker and Carroll 2011; Feltenstein and See 2007, Lynch 2008, Larson et al 2007, Anker et al 2012). Cocaine-primed reinstatement was reduced in female rats that were treated with P compared to vehicle-treated controls (Anker et al 2007), and allopregnanolone, a major metabolite of P, attenuated stess-induced reinstatement of cocaine-seeking behavior in female but not male rats (Anker and Carroll 2010).…”