Role of 5-HT in the regulation of the brain-pituitary-adrenal axis: effects of 5-HT on adrenocortical cells

Serotonin (5-HT) plays a pivotal role in the regulation of the brain-pituit ary-adrenal axis. In particular, 5-HT has been shown to control the activit y of hypothalamic CRF neurons and pituitary corticotrope cells through acti vation of 5-HT1A and (or) 5-HT2A/2C receptor subtypes. 5-HT, acting through 5-HT2 receptors, can also trigger the renin-angiotensin system by stimulat ing renin secretion and consequently can enhance aldosterone production. At the adrenal level, 5-HT produced locally stimulates the secretory activity of adrenocortical cells through a paracrine mode of communication. The pre sence of 5-HT in the adrenal gland has been demonstrated immunohistochemica lly and biochemically in various species. In the frog, rat, and pig adrenal gland, 5-HT is synthesized by chromaffin cells, while in the mouse adrenal cortex, 5-HT is contained in nerve fibers. In man, 5-HT is present in peri vascular mast cells. In vivo and in vitro studies have shown that 5-HT stim ulates corticosteroid secretion in various species (including human). The t ype of receptor involved in the mechanism of action of 5-HT differs between the various species. In frogs and humans, the stimulatory effect of 5-HT o n adrenocortical cells is mediated through a 5-HT4 receptor subtype positiv ely coupled to adenylyl cyclase and calcium influx. In the rat, the effect of 5-HT on aldosterone secretion is mediated via activation of 5-HT7 recept ors. Clinical studies indicate that 5-HT4 receptor agonists stimulate aldos terone secretion in healthy volunteers and in patients with corticotropic i nsufficiency and primary hyperaldosteronism. Local serotonergic control of corticosteroid production may be involved in the physiological control of t he activity of the adrenal cortex as well as in the pathophysiology of cort isol and aldosterone disorders.