Postnatal blockade of androgen receptors or aromatase impair the expression of stress hypothalamic-pituitary-adrenal axis habituation in adult male rats

SummarySex steroid hormones during development permanently alter, or organize, the brain and behavior, while during adulthood they act to reversibly modulate, or activate, physiology and behavior. Testosterone exerts both organizational and activational effects on the magnitude of the hypothalamic-pituitary-adrenal (HPA) axis response to acute stress. What has never been approached is how testosterone can organize habituation of the HPA axis, in which stress induced elevations in ACTH and corticosterone release decline over repeated exposures to the same stimulus. In the current study we examined HPA responses to repeated psychogenic stress in 65-day-old, adult male rats that received subcutaneous capsules containing the antiandrogen flutamide or the aromatase inhibitor 1,4,6-androstatriene-3,17-dione (ATD), introduced within 12 h of birth and removed on day 21 of weaning. An additional group of castrated, adult male rats were used to differentiate organizational from activational effects of testosterone. All treatment groups displayed smaller declines in ACTH in response to repeated restraint compared to control animals. Remarkably, the normal decline in corticosterone failed to occur in flutamide- and ATD-treated animals. By contrast, males that were castrated as adults showed a significant reduction in corticosterone after repeated stress. Taken together, these findings underscore an organizing influence of both androgen receptors and estrogen conversion on HPA habituation to repeated psychogenic stress, which appears to occur independent of the activational effects of testosterone.