The present study was undertaken to evaluate the serotonin (5-HT) receptor subtype(s) by which 5-HT acts on the pituitary to stimulate ACTH secretion. We tested the effects of the 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), the 5-HT(1C) receptor agonist metachloro-phenylpiperazine (m-CPP), which also binds to other 5-HT receptors with lower affinity, and the 5-HT(2/1C) receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) on basal, corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP)-stimulated ACTH release from primary rat anterior pituitary cell cultures. 5-HT, 8-OH-DPAT and DOI significantly increased basal ACTH release, an effect which was antagonized by 5-HT receptor antagonists. 5-HT and DOI were effective an nanomolar concentrations whereas 8-OH-DPAT was effective at higher concentrations. 5-HT, 8-OH-DPAT (both at 10 nmol/l) and DOI (at higher concentrations) blunted the stimulatory effect of CRH. The suppressive effects of 8-OH-DPAT and DOI on CRH-stimulated ACTH release were antagonized by (-)propranolol, a β-adrenergic receptor antagonist which binds the 5-HT(1A) receptor with elevated affinity, and ketanserin, a 5-HT2 receptor antagonist respectively. 5-HT, 8-OH-DPAT and DOI showed additive stimulatory effects with AVP but only at the highest concentration tested, whereas m-CPP potentiated AVP-induced ACTH release at concentrations of 1 nmol/l or more. This effect was antagonized by metergoline, a non-selective 5-HT receptor antagonist and mianserin, an antagonist which binds the 5-HT(1C) receptor with elevated affinity. Thus (1) 5-HT and selective 5-HT agonists such as 8-OH-DPAT, m-CPP and DOI modulate ACTH release by acting directly at the pituitary level; (2) serotonergic stimulation of basal ACTH release is mediated by both 5-HT2 and 5-HT(1A) receptors; (3) serotonergic inhibition of CRH-stimulated ACTH release is mediated by 5-HT(1A) and 5-HT2 receptors; whereas (4) serotonergic potentiation of AVP-stimulated ACTH release is mediated mainly by 5-HT(1C) receptors.
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism