Plasma progesterone levels and cocaine-seeking in freely cycling female rats across the estrous cycle

Abstract

Previous studies have reported sex and estrous cycle-dependent differences in the reinstatement of cocaine-seeking triggered by cocaine injections or drug-paired cues. However, the relationship between estradiol or progesterone levels and cocaine-seeking in a reinstatement model of relapse has not been explored. Thus, we examined changes in plasma hormone levels during cocaine-taking and -seeking behaviors in gonadally intact female rats. Rats self-administered cocaine (0.5 mg/kg infusion) during daily 2-h sessions, followed by extinction. For reinstatement, cocaine (0, 5, or 10 mg/kg, i.p.) was administered 30 min prior to testing. Vaginal smears and blood samples were collected prior to and during chronic cocaine self-administration, extinction, and reinstatement testing. Relative to non-estrous females, females in estrus showed greater responding during self-administration, extinction, and during cocaine-primed reinstatement. The highest progesterone levels were noted at the time of lowest cocaine-seeking (proestrus) and the lowest levels of progesterone occurred at the time of highest cocaine-seeking (estrus). In contrast, plasma estradiol levels did not show any clear pattern with cocaine-seeking. These data from an animal model of relapse supports recent clinical evidence that progesterone reduces subjective craving in cocaine-dependent women. Overall, these results suggest that progesterone administration may be a useful intervention for reducing the incidence of relapse.

Introduction

Epidemiological evidence suggests that significant sex differences exist in psychostimulant addiction. While men are more likely to have a cocaine abuse or dependence disorder (Brady and Randall, 1999), women begin using cocaine at an earlier age (Weiss et al., 1997), progress more rapidly from casual use to dependence (McCance-Katz et al., 1999, Westermeyer and Boedicker, 2000), and have higher rates of cocaine use than men (Griffin et al., 1989). In terms of relapse to cocaine use following a period of abstinence, women tend to have shorter cocaine-free periods (Griffin et al., 1989) and are more likely to relapse following stressful life events or depression (Back et al., 2005, Elman et al., 2001, McKay et al., 1996). Recent research has also demonstrated brain activation differences between abstinent men and women in response to events that can precipitate drug-craving and relapse, including exposure to cocaine-paired cues (Kilts et al., 2004) or stress-related imagery (Li et al., 2005). While psychosocial factors likely contribute to these differences, considerable preclinical data suggests that biological factors may also play a significant role in sex differences of cocaine-related behaviors.

Similar to humans, preclinical studies have revealed sex differences in cocaine-taking and -seeking in laboratory animals. Compared to males, female rats more rapidly acquire cocaine self-administration (Hu et al., 2004, Lynch and Carroll, 1999), exhibit higher breaking points on progressive ratio schedules of reinforcement (Carroll et al., 2002, Hecht et al., 1999, Roberts et al., 1989), display greater responding on short access (i.e., 2-h) schedules (Fuchs et al., 2005, Kippin et al., 2005) and greater cocaine intake on extended access (i.e., >6-h) schedules (Lynch and Taylor, 2004, Roth and Carroll, 2004). Recent data from animal models of relapse have demonstrated attenuated conditioned–cued reinstatement of cocaine-seeking in females (Fuchs et al., 2005), but enhanced cocaine-primed reinstatement relative to males (Kippin et al., 2005, Lynch and Carroll, 2000). Moreover, differences in self-administration (Hecht et al., 1999, Lynch et al., 2000, Roberts et al., 1989) and reinstatement (Fuchs et al., 2005, Kippin et al., 2005) behaviors vary as a function of the estrous cycle, with the greatest effects seen during the estrous phase, when levels of estrogen and progesterone are relatively low (Festa and Quinones-Jenab, 2004). While some evidence indicates a lack of effects of sex, gonadectomy, and gonadal hormones on cocaine self-administration (Caine et al., 2004), taken as a whole, previous studies suggest that sex differences in cocaine-related behaviors may be mediated, at least in part, by cyclic hormonal changes.

Several studies have demonstrated alterations in cocaine-motivated behaviors following ovariectomy and/or exogenous hormone administration. For example, estradiol administration reverses ovariectomy-induced decreases in self-administration (Hu et al., 2004, Jackson et al., 2006, Lynch et al., 2001; but see Grimm and See, 1997) and cocaine-primed reinstatement (Larson et al., 2005). On the other hand, acute progesterone treatment has been found to reverse estradiol's effects on the acquisition of cocaine self-administration (Jackson et al., 2006) and cocaine-primed reinstatement (Anker et al., 2006). These results suggest that estrogen and progesterone have opposing effects on the modulation of cocaine-seeking behavior. However, most previous studies have utilized ovariectomized female rats, which affects more than a single hormone. Moreover, exogenous replacement does not mimic the temporal pattern of ovarian hormone fluctuations found in human subjects.

We have previously utilized vaginal cytology procedures for the determination of estrous cycle phases (Fuchs et al., 2005, Kippin et al., 2005). However, measurement of ovarian hormone levels provides valuable information on estrous status, since chronic cocaine disrupts the estrous cycle in rats (Grimm and See, 1997, King et al., 1990, King et al., 1993) and the menstrual cycle in monkeys (Mello et al., 1997). Direct assessment of hormone levels also allows for comparison of hormone levels with behavioral responding. The relationship between estradiol or progesterone levels with cocaine self-administration and reinstatement of drug-seeking has been minimally studied. Therefore, the purpose of the present study was to examine plasma ovarian hormone levels during self-administration, extinction, and cocaine-primed reinstatement of cocaine-seeking in intact (non-ovariectomized) female rats.