Attenuation of cocaine-seeking by progesterone treatment in female rats

Abstract

SummaryClinical research suggests that gender differences exist in cocaine dependence. Similarly, preclinical studies have shown that female rats exhibit higher response rates during cocaine self-administration, early extinction, and cocaine-primed reinstatement of drug-seeking. These effects are also estrous cycle dependent and inversely related to plasma progesterone, in that proestrus females (high progesterone) exhibit less cocaine-seeking, while estrous females (low progesterone) show the greatest cocaine-seeking. Based on these findings, we hypothesized that progesterone would attenuate cocaine-seeking behavior in intact, freely cycling animals. The role of the estrous cycle on cocaine-seeking behavior during early (first acquisition day) versus late (last maintenance day) cocaine self-administration was also examined. Female, Sprague-Dawley rats self-administered cocaine (0.5 mg/kg/infusion, IV) along a FR1 schedule, followed by daily extinction sessions in the absence of cocaine reinforcement. Once responding was extinguished, rats received an injection of cocaine (10 mg/kg, IP) immediately prior to reinstatement testing. Progesterone (2 mg/kg, SC) or vehicle was administered 20 and 2 h prior to the first day of extinction (early cocaine withdrawal) and the reinstatement trials. To determine estrous cycle phase, we assessed vaginal cytology prior to the first acquisition and last maintenance days of cocaine self-administration, the first day of extinction training, and each reinstatement test. During early and late cocaine self-administration, proestrus and estrous females exhibited the greatest levels of active lever responding, respectively. A significant increase in responding also occurred during cocaine-primed reinstatement for estrous versus nonestrous females, an effect that was selectively attenuated by progesterone. However, progesterone was not effective at reducing cocaine-primed reinstatement for females in other phases of the estrous cycle, nor was it effective at reducing cocaine-seeking during early withdrawal. Taken together, these results suggest that progesterone may be a useful therapeutic for preventing relapse in abstinent female cocaine users, especially when the likelihood of relapse is greatest.

Sex Differences in Selecting Between Food and Cocaine Reinforcement are Mediated by Estrogen

“…Thus, similar to female rats, drug-experienced women appear to devalue food (and perhaps other natural reinforcers) relative to taking drugs to a greater extent than men, which is likely a significant contributor to the more severe profile of cocaine dependence that women display. Future projects are required to assess the role of estrogen in cocaine choice in a more detailed fashion, as well as examine the effect of other ovarian hormones (eg, progesterone and its metabolite, allopregnanolone) on cocaine choice, as this ovarian hormone has been shown to decrease motivation for cocaine in single reinforcer studies (Feltenstein et al, 2009;Anker et al, 2009).…”

Mifepristone in the Central Nucleus of the Amygdala Reduces Yohimbine Stress-Induced Reinstatement of Ethanol-Seeking

“…To date, the role of progesterone in drug-seeking behaviors has been mixed. Progesterone has been shown to be negatively correlated with drug-seeking behavior in cocaine-trained, female rats Feltenstein et al, 2009;Larson et al, 2007). However, it has been shown that the progesterone metabolite, allopregnanolone, can have both a stimulatory or inhibitory effect on ethanol intake depending on the dose administered and the drinking paradigm used (Ford et al, 2005;Janak et al, 1998;Morrow et al, 2001).…”

The Efficacy of Exercise to Attenuate Cocaine Relapse is Associated with Changes in Bdnf and Altered by Sex and Estrous Cycle Phase.

“…In humans, levels of cocaine craving vary across the menstrual cycle (Fox et al 2008) with evidence to suggest that these levels are influenced by the ratio of estradiol to progesterone (Sinha et al 2007). Similar findings have been observed in animal models in which levels of cocaine-seeking vary across the estrous cycle with the highest levels observed during estrus (Kippin et al 2005;Kerstetter et al 2008;Feltenstein and See 2007;Feltenstein et al 2011), a period when there are higher levels of estradiol compared to progesterone (Feltenstein et al 2009). Results have also shown that the incubation effect, the progressive increase in cocaine-seeking over protracted abstinence (Grimm et al 2001), is heightened and prolonged in estrus females compared to males and to females in non-estrus phases (Kersetter et al 2008).…”

“…This finding suggests that higher "doses" of exercise and/or environmental enrichment are required to compensate for hormonal influences during estrus (i.e. high estrogen levels as compared to progesterone; Feltenstein et al 2009) that would normally potentiate responding. In contrast, non-estrus females given prior limited access to a running wheel or extended access to a locked wheel demonstrated that less physical activity is required to reduce cocaine-seeking.…”

“…Although females in all phases of their estrous cycle exhibit incubation of cocaine craving (Kerstetter et al 2008), females tested during estrus (defined as high levels of estrogen relative to progresterone; Feltenstein et al 2009) maintain a potentiation in cocaine-seeking longer than those in other phases (Kippin et al 2005;Feltenstein and See 2007;Kersetter et al 2008). These findings are consistent with reports in ovariectomized rats supplemented with estradiol that displayed increased vulnerability during reinstatement testing conditions (for reviews see Anker and Carroll 2010;Anker 2009, andEvans 2007) and adds further support to the idea that hormonal status influences relapse vulnerability.…”