The effects of progestins on animal models of cocaine bingeing and relapse.

Abstract

Female gonadal hormones influence responses to stimulant drugs, and estrogen (EST) facilitates while progesterone (PROG) attenuates these responses. The PROG metabolite allopregnanolone (ALLO) also suppresses responses to cocaine, and it may be responsible for PROG's attenuating effects. The research included in this thesis is concerned with the influence of PROG and its metabolite ALLO on animal models of escalation or bingeing of cocaine of intake (Experiments 1 and 2) and reinstatement of extinguished drug seeking or relapse (Experiments 3, 4, and 5). Experiment 1 focused on the influence of PROG on the escalation of cocaine self-administration that occurs with long (6 h) daily access in ovariectomized (OVX) and gonadally intact female rats treated with either EST or VEH. Following the escalation procedure, treatment groups were compared on a progressive ratio (PR) schedule for several doses of cocaine. This research was extended to the PROG metabolite ALLO in Experiment 2a. Gonadally intact female rats were treated with ALLO or VEH and allowed to earn either i.v. cocaine infusions or sucrose deliveries under a long-access (LgA) escalation procedure. In Experiment 2b sucrose was used to determine the specificity of ALLO's effects on the escalation of cocaine self-administration, and in Experiment 2c control conditions were used to examine the effect of ALLO on locomotor activity and operant behavior reinforced by food. In Experiment 3 the effects of PROG on the reinstatement of cocaine-seeking behavior were examined in OVX and intact female rats that received EST or VEH treatment. In Experiment 4 the mechanism of PROG's effects was further studied by using finasteride, a 5-alpha reductase inhibitor that prevents the metabolism of PROG into ALLO. Finasteride (FIN) was administered concurrently with PROG to determine whether it could block the attenuating effects of PROG on cocaine-primed reinstatement, thus implicating ALLO in PROG's actions. Allopregnanolone was also tested on cocaine-primed reinstatement in male and female rats to examine possible sex-specific treatment effects. In the final experiment (Experiment 5), the effects of ALLO were examined on stress-induced reinstatement by injecting rats with yohimbine (YOH) to generate a stressful condition. Results from Experiment 1 indicated that EST facilitated while PROG attenuated the escalation of cocaine self-administration during LgA, but neither hormone affected cocaine-maintained responding under a PR schedule. Experiment 2a confirmed that ALLO also attenuated the escalation of cocaine self-administration, and 2b indicated that ALLO did not affect the escalation of intake of a nondrug reward (i.e., sucrose). Experiment 2c revealed that ALLO also had no effect on locomotor activity or operant food-reinforced behavior. Experiments 3 and 4 demonstrated that PROG and ALLO also decreased the reinstatement of cocaine-seeking behavior precipitated by i.p. injections of cocaine. Results from Experiment 4 further indicated that the attenuation of cocaine seeking by PROG may be attributed to its conversion into ALLO, as blocking this conversion with FIN prevented PROG's attenuating effects. In addition, the effects of ALLO were specific to females and did not extend to males. Finally, in Experiment 5, female rats exhibited greater reinstatement of cocaine seeking following a stressful stimulus (YOH) than males, and the attenuating effects of ALLO on this behavior were specific to females. Taken together, these results demonstrated a role for PROG and ALLO in suppressing the bingeing and relapse associated with cocaine abuse. These effects were specific to cocaine seeking in females (vs. males) and did not extend to behavior maintained by a nondrug rewards (i.e., sucrose or food) or locomotor activity.