Estradiol as a Mechanism for Sex Differences in the Development of an Addicted Phenotype following Extended Access Cocaine Self-Administration

Abstract

Women progress more rapidly after initial cocaine use to addiction as compared with men. Similarly, female rats appear to require less cocaine exposure before developing an addicted phenotype with evidence implicating estradiol as a potential mechanism. The goals of this study were to determine whether there are sex differences in the magnitude of the addicted phenotype under optimized conditions that induce its development in both males and females and to determine the role of estradiol in this effect. Following acquisition, intact male and intact and ovariectomized (OVX) female rats with and without estradiol replacement were given access to cocaine (1.5 mg/kg per infusion) under either extended access (ExA; discrete trial procedure, 4 trials/h, 24 h/day, 10 days) or short access (ShA) conditions (20 infusions maximum/day, 3 days). Motivation to obtain cocaine (0.5 mg/kg/infusion), as assessed under a progressive-ratio schedule, was then examined following a 2-week abstinence period. Results showed that following ExA self-administration, both males and females developed an addicted phenotype, with 9 of 11 males and 8 of 10 females showing a greater than 15% increase in levels of motivation to obtain cocaine as compared with ShA controls. In contrast, within the OVX groups, responding was enhanced from control levels after ExA self-administration in estradiol-replaced rats only. These results suggest that while females may have an enhanced vulnerability to developing an addicted phenotype, they may be similar to males once addiction has developed. These results also suggest that estradiol is critically involved in the development of an addicted phenotype in females.

Sex Differences in Animal Models: Focus on Addiction

“…Psychostimulants. Ovariectomized female rats with extended access using a discrete trials procedure failed to show greater motivation to take cocaine after extended access, and this effect was reversed by estradiol (Ramôa et al, 2013). Estradiol facilitated responding in a discrete-trials procedure during escalation and the motivation to take cocaine during abstinence (Ramôa et al, 2013).…”

“…However, once females develop an "addicted" phenotype, their behavior looks very similar to that of males (Ramôa et al, 2013;Perry et al, 2015).…”

Gender Considerations in Addiction: Implications for Treatment

“…Recent studies of the relationship between hormones and cocaine found that estrogen plays an important role in the transition from recreational drug use to cocaine dependence (19). Specifically, using real-time exposures to drug cues and drug use, Kennedy and colleagues (2013) found that women were more sensitive than men to such exposures.…”

Estradiol promotes the rewarding effects of nicotine in female rats

“…This is based on previous studies showing that OVX females display a reduction in cocaine IVSA that is normalized to intact female levels following E2 supplementation [19]. Also, another report revealed that OVX rats that received E2 supplementation displayed greater motivation to obtain cocaine relative to OVX rats that received vehicle [20]. …”