Chronic stress induced alterations of the HPA and serotonin receptor system in female animals: Modulation by antidepressants and estrogen.

Abstract

Depression is a psychiatric illness that affects twice as many women as men. A common finding in depressed patients is a dysregulation of the hypothalamic-pituitary adrenal (HPA) axis and serotonin receptors. The HPA axis is the classic close-loop negative feedback neuroendocrine system that responds to stress. Following exposure to chronic stress, male rats have alterations in the HPA axis and serotonin receptors that are similar to those seen in depression. These alterations include elevated baseline levels of corticosterone, a down-regulation of mineralocorticoid receptor (MR) and serotonin 1 a receptor (5-HT1a) mRNA in the hippocampus, and an increase of serotonin 2a (5-HT2a) mRNA in cortex. There is little known about these alterations in females. We therefore examined the effects of chronic stress in female animals. The experiments presented in this dissertation include direct comparisons between the effects of chronic unpredictable stress (CUS) in male and female animals and the effect of antidepressant or estrogen administration during CUS in female animals. We found that female animals respond to CUS exposure with an increase in baseline corticosterone, an increase in corticotrophin releasing hormone (CRH) mRNA levels in the hypothalamus, and an <italic>increase </italic> of MR mRNA in the hippocampus. Unlike male animals, female rats do not show alterations in 5-HT1a or 5-HT2a following CUS. Stress-induced disruption of the estrous cycle was also observed. The administration of fluoxetine, but not desipramine, during CUS was able to inhibit both the corticosterone elevations and the brain changes. We also found that estrogen administration to female rats can prevent the chronic stress-induced corticosterone elevation and the MR mRNA changes. In summary, we have determined that the brain response to chronic stress is different between male and female animals. We have also determined that different antidepressants have sexually dimorphic effect on the stress-induced brain alterations. Females are more sensitive to the anti-stress effects of fluoxetine than male rats. In addition, exogenous estrogen administration may function as an antidepressant by protecting the organism against the effects of stress in the brain. These data emphasize the difference between the chronic stress response between males and females.