Sex differences in serotonin (5-HT) 1A receptor regulation of HPA axis and dorsal raphe responses to acute restraint.

The serotonin (5-HT) 1A receptor subtype has been implicated as an important mediator for the stimulatory influence of serotonin on stress hypothalamic-pituitary-adrenal (HPA) activity, at least in males. Females show greater HPA axis responses to stress compared to males. To determine the nature by which the 5-HT 1A receptor contributes to the sex difference in stress, we examined neuroendocrine and cellular (Fos) responses in male and female rats receiving systemic injections of the 5-HT 1A receptor antagonist, WAY 100635, prior to acute restraint exposure. WAY decreased the corticosterone response in males, but not in females. In the paraventricular nucleus of the hypothalamus (PVH), WAY produced similar decrements in the restraint-induced activation (Fos) of neuroendocrine neurons in males and females. In contrast to the PVH, WAY administration increased total Fos activation in the dorsal raphe nucleus, but only in males. WAY also provoked higher Fos responses within subsets of dorsal raphe cells identified as serotonergic (tryptophan hydroxylase-, TPH-ir) in both males and females. These data provide evidence to suggest a differential influence of presynaptic 5-HT 1A receptors to regulate the stress-induced recruitment of non-serotonergic dorsal raphe neurons in males and females. At present, we cannot rule out a possible role for estrogen in females to alter 5-HT outflow to the HPA axis. There was a negative correlation between estrogen and Fos responses within TPH-positive cells in the dorsal raphe of WAY-administered females, whereas a positive correlation was found between estrogen and 5-HT 1A mRNA expression localized to the region of the zona incerta in close proximity to the PVH. As the raphe complex and 5-HT system impinge on several central autonomic, behavioral and neuroendocrine control systems, the current findings provide an important framework for future studies directed at sex differences in adaptive homeostatic responses.