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

P. A. Rittenhouse, E. A. Bakkum, A. D. Levy, Q. Li, M. Carnes, L. D. Van de Kar

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50 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1647-1655
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
StatePublished - 1994
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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