Figure 1. Schematic representation of the hypothalamic-pituitary-adrenal (HPA) axis. Hypophysiotropic neurons localized in the paraventricular nucleus (PVN) of the hypothalamus synthesize corticotropin-releasing factor (CRF) and vasopressin (AVP). In response to stress, CRF is released into hypophysial portal vessels that access the anterior pituitary gland. Binding of CRF to the CRF type 1 receptor (CRFR1) on pituitary corticotropes activates cyclic adenosine monophosphate (cAMP) pathway events that induce the release of adrenocorticotropic hormone (ACTH) into the systemic circulation. In the presence of CRF, AVP elicits synergistic effects on ACTH release that are mediated through the vasopressin V_1b receptor. Circulating ACTH binds to the melanocortin type 2 receptor (MC2-R) in the adrenal cortex where it stimulates glucocorticoid synthesis and secretion into the systemic circulation. Glucocorticoids regulate physiological events and inhibit further HPA axis activation (red lines) through intracellular receptors that are widely distributed throughout the brain and peripheral tissues. IP3, inositol triphosphate; DAG, diacylglycerol .