Fig. 2: Major neuroendocrine components of the hypothalamic–pituitary–adrenal axis. Hypothalamic neurons synthesize and release corticotropin releasing hormone (CRH), which is transported to the anterior pituitary via the hypothalamic-hypophyseal portal vessels, interacts with pro-opiomelanocortin (POMC) producing cells and stimulates the synthesis and release adrenalcorticotropin (ACTH), β -lipotropin (β -LPH) and β -endorphin. CRH also interacts with hypothalamic endorphinergic neurons and stimulates the release of β -endorphin in the brain. ACTH stimulates cells of the adrenal cortex to increase the synthesis and release of cortisol, and this increase in plasma cortisol inhibits the release of CRH and ACTH via a negative-feedback mechanism. The release of CRH is also inhibited by opioidergic and GABAergic neurons and stimulated by serotonergic (5-HT) and noradrenergic (NE) neurons. Ethanol stimulates the release of CRH, and this leads to increased release of β -endorphin, both by the pituitary and the hypothalamus.