Gender difference in cocaine-induced HPA axis activation.

The study investigates the influence of gender on the activation of the hypothalamo-pituitary-adrenal (HPA) axis by cocaine and other monamine uptake inhibitors. Drug-induced secretion of adrenocorticotrophic hormone (ACTH) was used to pursue this question. Cocaine produced a dose-related rise in serum ACTH levels in both male and female rats, but the rise was significantly greater in females than in males. Females also showed enhanced HPA axis activation following administration of the dopamine uptake inhibitor GBR 12909, the serotonin uptake inhibitor fluoxetine, and the norepinephrine uptake inhibitor desipramine. No gender difference in HPA axis activation was observed in a dose-response study of cocaine-induced HPA activation in 10 day old rats. Ovariectomy of females decreased the ACTH response to cocaine, but castration did not affect the response of males. To evaluate the role of the pituitary in this gender difference, ACTH levels were determined after corticotropin-releasing factor (CRF) administration. Females showed greater ACTH responses to CRF than males. These studies demonstrate that female rats show exaggerated HPA responses to monoamine uptake inhibitors and that enhanced pituitary responsivity to CRF contributes to this gender difference.