Differential effects of allopregnanolone on the escalation of cocaine self-administration and sucrose intake in female rats

Abstract

Rationale: Evidence suggests that the progesterone metabolite allopregnanolone (ALLO) decreases cocaine seeking in animal models of relapse.

Objective: The purpose of this study was to examine the effects of ALLO on an animal model of cocaine and sucrose bingeing (escalation). Allopregnanolone's effects on yohimbine-induced sucrose intake were also examined. In a separate group of animals, dose interactions between ALLO and cocaine were examined with an abbreviated procedure, a short access progressive ratio (PR) schedule for cocaine reinforcement.

Methods: Female rats were treated with ALLO (15 mg/kg, s.c.) or vehicle (VEH) and trained to lever press for cocaine infusions (0.4 mg/kg) under an extended-access procedure. In a separate condition, other ALLO- and VEH-treated female rats self-administered orally delivered liquid sucrose. Allopregnanolone and VEH treatment was then discountinued and the sucrose-maintained rats were administered priming injections of saline, yohimbine, or yohimbine + ALLO. For the PR condition, rats were first treated with VEH until reaching stability at four doses of cocaine (0.2, 0.4, 0.8, and 1.6 mg/kg in mixed order). Subsequently, rats re-established their baseline cocaine intake at the four cocaine doses following treatment with each of two counterbalanced doses of ALLO (15 and 30 mg/kg).

Results: ALLO significantly blocked the escalation of cocaine self-administration but did not reliably affect intake of sucrose under a similar condition or affect cocaine intake at several doses under a PR schedule. Yohimbine significantly increased sucrose intake while ALLO failed to attenuate this increase.

Conclusion: These findings indicate that ALLO protects against binge-like patterns of cocaine intake but does not reduce sugar intake that is acutely increased by yohimbine in females.

Fig. 1

Data represent the mean (±SEM) cocaine infusions self-administered by female rats each day of the LgA phase. Horizontal lines indicate 3-day intervals during which VEH-treated rats earned more infusions than ALLO-treated rats (p<0.05). (†) p<0.05 block 1 <blocks 3–7 in the VEH group

Fig. 2. Mean (+SEM) hourly cocaine infusions (per 6-h session) self-administered by VEH- and ALLO-treated rats during the 1st, 7th, 14th, and 21st days of LgA. Horizontal lines indicate significant group differences across all of the hours during the 14th and 21st days of LgA

Fig. 3

Mean (±SEM) cocaine infusions self-administered by female rats during ShA sessions before (black bars) and after (white bars) the escalation phase. (Aterisk) p<0.05 post LgA vs. pre LgA within group

Fig. 4

Data represent the mean (±SEM) sucrose deliveries self-administered by VEH- and ALLO-treated female rats each day of the LgA phase

Fig. 5. Mean (+SEM) hourly sucrose deliveries (per 6 h session) self-administered by VEH- and ALLO-treated rats during the 1st, 7th, 14th, and 21st days of LgA

Fig. 6

Mean (± SEM) sucrose deliveries following saline (S) or yohimbine (Y) priming injections during 2-h sessions. Asterisks indicate significantly greater responding following Y compared to S priming injections (p<0.05)