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Sex differences in the effects of allopregnanolone on yohimbine-induced reinstatement of cocaine seeking in rats

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Abstract

Sex differences exist in several aspects of cocaine abuse, and recent research suggests that this may be due, in part, to differential sensitivity to stress. Women, compared to men, exhibit greater stress-induced cocaine craving and responses to both cocaine and stress fluctuate during phases of the hormonal cycle. The goal of the present study was to compare male and female rats on the maintenance and extinction of cocaine seeking and on an animal model of stress-induced relapse by administering the pharmacological stressor yohimbine. An additional goal was to examine possible sex-specific treatment effects of the progesterone metabolite, allopregnanolone, on yohimbine-induced reinstatement. Male and female rats were trained to lever press for i.v. infusions of cocaine (0.4 mg/kg). Following a 14-day maintenance period, cocaine solutions were replaced with saline, and rats were allowed to extinguish lever pressing. Subsequently, rats were administered saline, yohimbine (2.5 mg/kg), or allopregnanolone (15 mg/kg) + yohimbine (2.5 mg/kg) priming injections on separate days using a within-subjects reinstatement procedure. The results indicated that females were more resistant to extinction than male rats and that both groups reinstated cocaine seeking following injections of yohimbine; however, female rats responded more than males to yohimbine-priming injections. Additionally, allopregnanolone blocked yohimbine's potentiating effect on responding in females but not males. These results suggest that females may be more sensitive than males to stress-induced reinstatement of cocaine-seeking behavior, and the progesterone metabolite, allopregnanolone, offers protection against this vulnerability.

Introduction

There are numerous examples of sex differences in cocaine abuse. Women, compared to men, are more likely to initiate cocaine use at an earlier age (Chen and Kandel, 2002), and they have greater difficulty abstaining from cocaine than males (Ignjatova and Raleva, 2009, Kosten et al., 1993). Research also indicates the presence of sex differences in stress reactivity, a major factor in drug abuse liability (Sinha, 2008) and a leading cause of relapse (Sinha, 2007, Sinha, 2009, Sinha and Li, 2007). Indeed, females exhibit greater levels of craving for cocaine and other drugs of abuse than males following the presentation of stressful stimuli (for review see Fox and Sinha, 2009).

Recent findings have further implicated estrogen and progesterone in mediating responses to cocaine in women. This research indicates that the effects of these hormones are opposite in direction; estrogen facilitates, while progesterone and its metabolites allopregnanolone attenuate these responses. For example, during the menstrual cycle, when endogenous estrogen levels are at their highest (i.e., follicular phase), women reported an increase in cocaine-induced positive subjective effects, while progesterone treatment prevented this facilitation (for reviews see Evans, 2007, Terner and de Wit, 2006). Similar findings have been reported with female animals, and in these studies estrogen treatment facilitated, while progesterone or allopregnanolone treatment attenuated the acquisition (Hu and Becker, 2008, Jackson et al., 2006, Lynch et al., 2001), escalation (Larson et al., 2007) and reinstatement (Anker et al., 2007, Anker et al., 2009, Feltenstein et al., 2009, Jackson et al., 2006, Larson and Carroll, 2007, Larson et al., 2005) of cocaine-seeking behavior in female rats.

Progesterone is also involved in modulating craving elicited by stressful stimuli in women. In a study conducted by Sinha et al. (2007), women were separated into three groups that had high, medium, or low levels of circulating progesterone, corresponding to the midluteal, early luteal, and follicular phases of their menstrual cycle, respectively. Women reported less stress-induced cocaine craving when they had high (midluteal) or moderate (luteal), compared with low (follicular) levels of circulating progesterone. The anxiolytic effects of progesterone may be attributed to its rapid metabolism into allopregnanolone, a more potent anxiolytic (Russell et al., 2008). However, little is known regarding how allopregnanolone affects stress as it relates to cocaine addiction. It is also not known whether this effect applies to males.

The purpose of the present study was to examine the effects of allopregnanolone in an animal model of stress-induced reinstatement of cocaine seeking by administering the pharmacological stressor, yohimbine. Female and male rats were trained to lever press for i.v. infusions of cocaine for 14 days and were then allowed to extinguish lever pressing for 21 days. Subsequently, rats were tested using a within-subjects reinstatement procedure by administering priming injections of yohimbine (Y), allopregnanolone + yohimbine (A + Y), or saline (S) at the beginning of each session.

Section snippets

Subjects

Gonadally intact female (n = 11) and male (n = 8) 90-day-old Wistar rats (Harlan Sprague–Dawley, Inc., Indianapolis, IN) weighing 250–300 g and 350–400 g, respectively, served as subjects in the present study. During testing, the estrous cycle was allowed to randomly vary in female rats so that results would generalize to a range of hormonal conditions. Upon arrival, rats were pair-housed in plastic cages where they had access to ad libitum food and water. Rats were allowed to acclimate for at least

Maintenance and extinction

Females and males responded a similar number of times for i.v. cocaine infusions during the maintenance condition [mean (±SEM) females = 50.9 (±3.7), males = 54.4 (±8.8)], and the number of responses was stable across the 14 days (Fig. 1, left). During the extinction condition, females responded more on the lever previously associated with i.v. cocaine self-administration than males (F1,56 = 4.64, p < 0.05), while both groups decreased responding over the 21 days (Fig. 1, right). In addition, both

Discussion

In the present study, the effects of allopregnanolone were examined on yohimbine-induced reinstatement of cocaine-seeking behavior in female and male rats. There were no sex differences during the maintenance of cocaine self-administration, however; females were more resistant to extinction of lever pressing following the removal of cocaine. This result supports previous work showing heightened extinction responding in female compared to male rats (Kerstetter et al., 2008, Kippin et al., 2005,

Role of funding source

This research was supported by the National Institute on Drug Abuse (NIDA) grants, R01 DA 003240-25, R01 DA019942-2, K05 015267-07 (MEC) and F31 DA 023301-02 (JJA). NIDA had no further role in the study design; in the collection, analysis, and interpretation of data; in writing; nor in the decision to submit the manuscript for publication.

Contributors

Justin Anker and Marilyn Carroll were involved in the design of the experiment, data analysis, graphic presentation, and manuscript preparation. Both authors were involved in the final preparation of the manuscript, and have approved the final version.

Conflict of interest

No conflict of interest.

Acknowledgements

The authors would like to thank Luke Gliddon, Nathan Holtz, Emily Kidd, Brandon Knight, Kinner Patel, Paul Regier, Amy Saykao, Rachael Turner, and Natalie Zlebnik for their technical assistance.

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