Biological Basis of Sex Differences in the Propensity to Self-administer Cocaine

Abstract

Women are at greater risk for cocaine addiction than are men, and female rats similarly show a greater propensity to self-administer cocaine than do male rats. This could be due to the intrinsic sex differences in brain organization, to the activational effects of circulating gonadal hormones, or both. For example, estradiol enhances dopamine release in the striatum and nucleus accumbens, and facilitates the behavioral sensitization induced by repeated cocaine exposure. We report here that independent of circulating gonadal hormones, female rats acquire cocaine self-administration behavior more rapidly, and they self-administer more cocaine at a faster rate than do male rats. This indicates that there is an intrinsic difference between male and female subjects in the neural systems mediating drug-seeking behavior due to sexual differentiation of the brain. Furthermore, we find that the administration of estradiol to gonadectomized female subjects greatly facilitates the acquisition of cocaine self-administration. These data demonstrate that both intrinsic sex differences in brain organization and the actions of circulating estradiol contribute to increased vulnerability for cocaine use in female subjects.

Acquisition of cocaine self-administration in ovariectomized female rats: Effect of estradiol dose or chronic estradiol administration

“…As described previously (Hu et al, 2004), on the scheduled testing day, animals received 0.1 ml of peanut oil (OVX group and OVX+E Pellet group) or 17 β-estradiol (E) treatment in 0.1 ml peanut oil (s.c.) 30 min before the self-administration testing session (doses are given below for the acute E treatment group). Daily 1-hour sessions of self-administration testing were given for five consecutive days followed by two days off for five weeks.…”

“…Female rats show greater behavioral sensitization after repeated cocaine injections than do male rats (Glick et al, 1984;van Haaren et al, 1991;Chin et al, 2002;Hu et al, 2003). They also acquire cocaine self-administration more readily than male rats (Lynch et al, 1999;Lynch et al, 2001;Carroll et al, 2002;Hu et al, 2004).…”

“…Estradiol (E) is thought to modulate the reinforcing effects of cocaine (Roberts et al, 1989;Grimm et al, 1997;Lynch et al, 2000;Lynch et al, 2001;Carroll et al, 2002;Hu et al, 2004;Jackson et al, 2006). For example, female rats will work harder for cocaine during estrus than during other phases of the estrous cycle (Roberts et al, 1989;Carroll et al, 2002) and E treatment given to ovariectomized (OVX) rats enhances the motivation to self-administer cocaine (Becker et al, 2007).…”

“…When various doses of cocaine are available, female rats choose higher doses of cocaine during estrus than during other phases of the estrous cycle (Lynch et al, 2000). OVX females given E replacement acquire cocaine self-administration faster, and at lower doses of cocaine, than do OVX females or male rats treated with vehicle (Hu et al, 2004). Finally, E does not enhance cocaine self-administration in male rats (Jackson et al, 2006).…”

Sex Differences in Neurochemical Effects of Dopaminergic Drugs in Rat Striatum

“…Our laboratory and others have shown that indirect dopamine agonists like cocaine induce greater behavioral (Bowman and Kuhn, 1996;Walker et al, 2001a) and neuroendocrine (Walker et al, 2001b) effects in female than male rats. Female rats trained to self-administer cocaine on a progressive ratio schedule have higher break points than males (Roberts et al, 1987;Carroll et al, 2002), and acquisition, maintenance and reinstatement of cocaine self-administration are greater in female rats Carroll, 1999, 2000;Hu et al, 2004). However, Caine et al (2004) using a relatively hightraining dose of cocaine found that male rats acquired self-administration earlier than females.…”