Grant: Operating Grant

The hypothalamic-pituitary-adrenal (HPA) axis is a hormonal system that regulates glucocorticoid steroid hormone secretion that is essential for maintaining physiological balance in the face of real or perceived threats on the body. Glucocorticoid hypersecretion, however, has been implicated in the development of mood disorders. The incidence of depressive disorders is higher in women compared to men, yet the mechanism responsible for this disparity is unknown. Stressful experiences and alterations in the serotoninergic (5-HT) neurotransmitter system have been implicated as factors contributing to depression. The majority of studies on 5-HT and stress interactions, however, have been conducted in male subjects. Thus, most of what we think we understand about stress and depression may not be the same between males and females. To study this possibility we use anatomical techniques and assess neuroendocrine and behavioral responses using a rodent model. Previous studies indicate that the 5-HT 1A receptor is tied to the stimulatory effects of serotonin on the HPA axis, and plays an important role in the mechanism of action of antidepressant drugs. Our recent findings suggest brain-specific, sex differences in serotonergic regulation of the HPA axis. Males, but not females, adapt to repeated stress exposure by showing decreased glucocorticoid responses. We also have new evidence to show that male and females differentially rely on the 5-HT 1A receptor to regulate glucocorticoid secretion. We hypothesize that normal adaptation to stress occurs as a consequence of changes in 5-HT 1A receptor function, and that this mechanism may help us understand the substrate underlying individual and gender-based differences in susceptibility to stress-related disorders.