Sex differences in stress-related receptors: ″micro″ differences with ″macro″ implications for mood and anxiety disorders

Abstract

Stress-related psychiatric disorders, such as unipolar depression and post-traumatic stress disorder (PTSD), occur more frequently in women than in men. Emerging research suggests that sex differences in receptors for the stress hormones, corticotropin releasing factor (CRF) and glucocorticoids, contribute to this disparity. For example, sex differences in CRF receptor binding in the amygdala of rats may predispose females to greater anxiety following stressful events. Additionally, sex differences in CRF receptor signaling and trafficking in the locus coeruleus arousal center combine to make females more sensitive to low levels of CRF, and less adaptable to high levels. These receptor differences in females could lead to hyperarousal, a dysregulated state associated with symptoms of depression and PTSD. Similar to the sex differences observed in CRF receptors, sex differences in glucocorticoid receptor (GR) function also appear to make females more susceptible to dysregulation after a stressful event. Following hypothalamic pituitary adrenal axis activation, GRs are critical to the negative feedback process that inhibits additional glucocorticoid release. Compared to males, female rats have fewer GRs and impaired GR translocation following chronic adolescent stress, effects linked to slower glucocorticoid negative feedback. Thus, under conditions of chronic stress, attenuated negative feedback in females would result in hypercortisolemia, an endocrine state thought to cause depression. Together, these studies suggest that sex differences in stress-related receptors shift females more easily into a dysregulated state of stress reactivity, linked to the development of mood and anxiety disorders. The implications of these receptor sex differences for the development of novel pharmacotherapies are also discussed.

Figure 1

This schematic illustrates sex differences in CRF₁ trafficking in LC dendrites [133]. Under conditions of excessive release of CRF (green), CRF₁ receptors (blue) internalize in male neurons (left). This effect reduces neuronal responses to CRF in males. In females (right), CRF₁ receptors fail to internalize under conditions of CRF hypersecretion, resulting in greater neuronal responses to CRF in this group.

Figure 2

This schematic depicts the role of GR translocation in glucocorticoid negative feedback. Glucocorticoids readily cross the plasma membrane to bind nuclear GRs. GRs then are shuttled into the nucleus by multiple co-chaperones (in green), such as PPID and FKBP52. Once inside, GRs bind to glucocorticoid response elements (GREs) on genes to repress transcription of CRF and precursors for ACTH. Other co-chaperones (in red), including Bag1 and Fkbp5, inhibit GR translocation, an effect which can attenuate negative feedback.