Figure 1.

Proposed scenario for MA effects on the HPA axis and behavior. MA activation of the HPA axis involves release of CRF from neurosecretory cells of the paraventricular hypothalamic nucleus and subsequent release of ACTH and glucocorticoids from the anterior pituitary and adrenal cortex, respectively. Release of glucocorticoids is greater in females than males. High levels of glucocorticoids may contribute to alterations in HPA axis associated genes/proteins (CRF, AVP, GR). These effects in the brain may subsequently alter HPA axis function (release of stress hormones) and in turn affect anxiety- and depressive-related behaviors often observed during withdrawal. Altered HPA axis function and mood behaviors may provide bi-directional positive feedback, thereby exacerbating these effects. Altered mood behaviors can lead to a need to alleviate an aversive mood state, thereby increasing the risk of further MA use as a means to reduce internal distress. The relationship between the elevated glucocorticoid response to MA in females and brain and behavioral consequences are currently unknown.