Serotonergic Regulation of Adrenocortical Function

Abstract

Serotonin (5-HT) plays a pivotal role in the regulation of the hypothalamo-pituitary-adrenal axis. In particular, 5-HT is involved in the stimulation of ACTH secretion during stress. Recent data indicate that, at the adrenal level, 5-HT acts as a local regulator of corticosteroid secretion. The presence of 5-HT in the adrenal gland has been demonstrated immunohistochemically and biochemically in various species including frog, mouse, rat and human. In the mouse, 5-HT has been detected in nerve fibers while, in the frog and rat, 5-HT appears to be sequestered in chromaffin cells. In man, 5-HT is stored in perivascular mast cells. In vivo and in vitro studies have shown that 5-HT stimulates mineralo- and glucocorticoid secretion from adrenal cells. In rat, the type of receptor involved in the corticotropic effect of 5-HT is still controversial. In the frog and the human, the effect of 5-HT on the adrenal cortex is mediated through a 5-HT4 receptor subtype positively coupled to adenylyl cyclase and calcium influx. Clinical studies indicate that 5-HT4 receptor agonists stimulate aldosterone secretion in healthy volunteers and in patients with aldosterone disorders. The 5-HT4 receptor agonist cisapride and angiotensin II exert additive effects on aldosterone secretion. In contrast, cisapride has no influence on ACTH-induced aldosterone release. Collectively, these findings suggest that intra-adrenal 5-HT stimulates the secretory activity of adrenocortical cells through a paracrine mode of communication involving a 5-HT4 receptor type. Serotonergic control of corticosteroid production may be involved in the physiological control of the activity of the adrenal cortex, in particular during inflammatory stress. 5-HT may also be implicated in the pathophysiology of aldosterone disorders.

Screening for membrane hormone receptor expression in primary aldosteronism

“…Accordingly, a strong stimulating effect of serotonergic substances have been described for aldosterone secretion and to a weaker degree for cortisol secretion (31,32). Furthermore, in vitro and in vivo studies have demonstrated the presence of 5-HT4 receptors in APA (23,27).…”

5‐HT4 receptors on cholinergic nerves involved in contractility of canine and human large intestine longitudinal muscle

“…In bioassays, it was demonstrated that 5-HT 4 receptors are abundantly present in the gut (for review: Hegde & Eglen, 1996), but were also found in human brain (Reynolds et al, 1995; by means of binding studies), heart (Kaumann, 1993), adrenal cortex (Lefebvre et al, 1998) and bladder (Candura et al, 1996). In the gut, rat oesophagus muscularis mucosae contains smooth muscle 5-HT 4 receptors mediating relaxation (Baxter et al, 1991), an e ect suggested to be absent in the guinea-pig and dog (Cohen et al, 1994).…”

Dissociable Hormonal, Cognitive, and Mood Responses to Neuroendocrine Challenge: Evidence for Receptor-Specific Serotonergic Dysregulation in Depressed Mood

“…Instead one would have to posit that the mechanism accounting for the differences in the ACTH/cortisol ratio induced by both 5-HT agonists is occurring at the level of the adrenal gland. Specifically, the data suggest that m-CPP increases cortisol release not only by stimulating ACTH secretion but also by acting directly at the level of the adrenocortical cell (Contesse et al, 2000;Lefebvre et al, 1998). Alternatively, the differential effects on cortisol release could be produced if ipsapirone both stimulates ACTH release and attenuates the action of ACTH on cortisol secretion.…”