Resumo

Historically, data on addiction have been obtained from males. Recent data have demonstrated that females have an altered course to addiction as compared to males with evidence to suggest that ovarian hormones may underlie these differences. Most sex difference studies have focused on early stages of addiction and therefore less is known about sex and hormonal influences in later stages. This study examined the influence of ovarian hormones as a mechanism underlying sex differences in vulnerability at both an early and a later stage of cocaine addiction. In order to mimic an early versus a late stage of addiction, rats were given access to cocaine under either short (ShA) or extended access (ExA) conditions which have been shown previously to produce either relatively consistent and low levels of cocaine self-administration (SA) or high levels and binge patterns of intake, respectively. Importantly, the ExA model that we use also produces subsequent increases in motivation for cocaine. Adult female ovariectomized (OVX) rats (n=3-6/group) were trained to SA cocaine (1.5 mg/kg/infusion) under a fixed ratio 1 schedule with a maximum of 20 infusions per session. Once rats acquired cocaine SA, rats were given either ShA to cocaine consisting of 3 more fixed ratio 1 sessions or ExA to cocaine consisting of 10 days of 24h access to cocaine infusions under a discrete trial procedure (4 infusions/hr). Following 14 days of abstinence, cocaine motivation was assessed by measuring responding under a progressive-ratio (PR) schedule. Additional control groups of OVX females with and without estradiol (n=5/group) were tested on PR responding for sucrose reward. Preliminary data show that both groups of OVX female rats demonstrate a higher motivation for cocaine following ExA SA compared to following ShA SA. Additionally, following ExA SA OVX females rats supplemented with estradiol show higher motivation for cocaine as compared to OVX female rats receiving vehicle. No significant differences were observed for responding for sucrose. Based on evidence suggesting that estradiol enhances vulnerability to the reinforcing effects of cocaine in females by enhancing dopaminergic (DAergic) signaling in the reward pathway (i.e. nucleus accumbens (NAc)), we are currently examining the effects of intra-accumbens infusions of both D1 (SCH 23390) and D2 (Eticlopride) antagonists on motivation for cocaine in OVX female rats with and without estradiol replacement to further understand the mechanism by which estradiol enhances motivation for cocaine in females.