Sex differences in cocaine-stimulated motor behavior: disparate effects of gonadectomy.

Sex differences in biological substrates of drug use and addiction are poorly understood. The present study investigated sexual dimorphisms in motor behavior following acute cocaine administration (10, 20, or 40 mg/kg, i.p.). Cocaine increased stereotypy rating, horizontal and vertical activity in both sexes, and effects were always greater in females than males. A population analysis using data from multiple experiments indicated that horizontal activity scores were normally distributed in males but not in females. Gonadectomy induced disparate effects on cocaine-stimulated motor behavior. Population analysis indicated that castrated males exhibited more horizontal activity and stereotypy than shams. Ovariectomy did not affect cocaine-stimulated stereotypy but did attenuate horizontal activity in a subset of rats that had not been vaginally lavaged. In summary, gonadectomy effects were sex and behavioral topography specific and indicate that activational effects of gonadal hormones partially mediate the robust sex differences in cocaine-stimulated open-field behavior.

Effect of ovarian hormones and estrous cycle on stimulation of the hypothalamo-pituitary-adrenal axis by cocaine.

Cocaine is known to exert sexually dimorphic HPA axis effects in rats and to disrupt estrous cyclicity and/or fertility in rats, nonhuman primates, and humans. The present studies investigated the reciprocal interactions between ovarian hormones and HPA axis responses to cocaine. Thirty minutes after injection, cocaine (15 mg/kg i.p.) increased serum ACTH and corticosterone more in cycling than ovariectomized females or male rats. ACTH and corticosterone were highest in proestrus when estradiol was elevated. Cocaine did not alter serum estradiol in females or testosterone in males but did stimulate progesterone secretion in both sexes. Cocaine-stimulated progesterone secretion was significantly greater in females than in males or ovariectomized females, and greater in proestrous than diestrous 1 rats. Cocaine stimulated corticosterone and progesterone secretion in sham-adrenalectomized, but not adrenalectomized rats, indicating that the adrenal gland and not the ovary is the source of cocaine-stimulated progesterone. Estrogen influenced cocaine-stimulated progesterone secretion more than corticosterone, suggesting different release mechanisms for the two steroids in the adrenal. These results suggest that adrenally derived progesterone could contribute to cocaine-induced physiological changes, including inhibited gonadotropin release.