Evidence that ACTH secretion is regulated by serotonin(2A/2C) (5- HT(2A/2C)) receptors

The present study characterized the serotonin (5-HT) receptor subtypes mediating adrenal corticotropic hormone (ACTH) and corticosterone responses to 5-HT agonists in conscious rats. The 5-HT(2A)/5-HT(2C) agonist (±-1- (2,5-dimethoxy-4-iodophenyl)-2-aminopropane HC1 (DOI) increased plasma ACTH and corticosterone in a dose-dependent manner. The 5-HT(2A)/5-HT(2C) antagonist ritanserin (0.01 and 0.1 mg/kg sc) inhibited the DOI-induced increase in plasma ACTH, but not corticosterone. Low doses of spiperone (0.01 and 0.1 mg/kg sc) significantly reduced the ACTH response to DOI. Because spiperone has a higher affinity for 5-HT(2A) than 5-HT(2C) receptors, these data suggest that DOI stimulates ACTH secretion through 5-HT(2A) receptors, 5-methoxy-3-[1,2,3,4-tetrahydro-4-pyridinyl]-1H-indole (RU 24969) is a potent 5-HT(1A/1B) and moderate 5-HT(2C) agonist that also has been suggested to release 5-HT. However, p-chlorophenylalanine (PCPA) did not reduce the effect of RU 24969 on plasma ACTH, suggesting that RU 24969 only acts as a direct agonist. 6-methyl-1-[1-methylethyl]ergoline-8-carboxylic acid (LY53857) injected into the lateral cerebral ventricles (i.c.v.) inhibited the ACTH, but not corticosterone response to peripheral injection of RU 24969, suggesting that central 5-HT(2A/2C) receptors mediate the ACTH response. LY53857 injection (i.c.v.) also inhibited the effect of p-chloroamphetamine (i.c.v.) on plasma ACTH. However, the corticosterone response was not inhibited by LY53857, suggesting a distinct location of 5-HT receptors regulating corticosterone secretion. Lesions using the cell-selective neurotoxin ibotenic acid in the hypothalamic paraventricular nucleus significantly lowered the ACTH response to both RU 24969 (43% decrease) and p-chloroamphetamine (26% decrease). In contrast, lesions in the dorsomedial or ventromedial nuclei did not alter the ACTH response to p- chloroamphetamine. The corticosterone response followed the ACTH response in each of these experiments. The results from these experiments suggest the following: (1) a greater role exists for 5-HT(2A) than 5-HT(2C) receptors in the hypothalamus in mediating DOI's effect on ACTH secretion; (2) a peripheral 5-HT receptor is important in stimulating corticosterone secretion, independent or separate from control by ACTH and (3) relatively modest increases in plasma ACTH produce maximal increases in plasma corticosterone.