EVIDENCE THAT ACTH-SECRETION IS REGULATED BY SEROTONIN(2A 2C) (5-HT2A/2C) RECEPTORS/

The present study characterized the serotonin (5-HT) receptor subtypes mediating adrenal corticotropic hormone (ACTH) and corticosterone res ponses to 5-HT agonists in conscious rats. The 5-HT2A/5-HT2C agonist ( +/--1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HC1 (DOl) increased plasma ACTH and corticosterone in a dose-dependent manner. The 5-HT2A/ 5HT(2C) antagonist ritanserin (0.01 and 0.1 mg/kg sc) inhibited the DO l-induced increase in plasma ACTH, but not corticosterone. Low doses o f spiperone (0.01 and 0.1 mg/kg sc) significantly reduced the ACTH res ponse to DOl. Because spiperone has a higher affinity for 5-HT2A than 5-HT2C receptors, these data suggest that DOl stimulates ACTH secretio n through 5-HT2A receptors. 5-methoxy-3-[1,2,3,4-tetrahydro-4-pyridiny l]-1 H-indole (RU 24969) is a potent 5-HT1A/1B and moderate S-HT2C ago nist that also has been suggested to release 5-HT. However, p-chloroph enylalanine (PCPA) did not reduce the effect of RU 24969 on plasma ACT H, suggesting that RU 24969 only acts as a direct agonist. and 6-methy l-1-[1-methylethyl]ergoline-8-carboxylic acid (LY53857) injected into the lateral cerebral ventricles (i.c.v.) inhibited the ACTH, but not c orticosterone response to peripheral injection of RU 24969, suggesting that central 5-HT2A/2C receptors mediate the ACTH response. LY53857 i njection (i.c.v.) also inhibited the effect of p-chloroamphetamine (i. c.v.) on plasma ACTH. However, the corticosterone response was not inh ibited by LY53857, suggesting a distinct location of 5-HT receptors re gulating corticosterone secretion. Lesions using the cell-selective ne urotoxin ibotenic acid in the hypothalamic paraventricular nucleus sig nificantly lowered the ACTH response to both RU 24969 (43% decrease) a nd p-chloroamphetamine (26% decrease). In contrast, lesions in the dor somedial or ventromedial nuclei did not alter the ACTH response to p-c hloroamphetamine. The corticosterone response followed the ACTH respon se in each of these experiments. The results from these experiments su ggest the following: (1) a greater role exists for 5-HT2A than 5-HT2C receptors in the hypothalamus in mediating DOl's effect on ACTH secret ion; (2) a peripheral 5-HT receptor is important in stimulating cortic osterone secretion, independent or separate from control by ACTH and ( 3) relatively modest increases in plasma ACTH produce maximal increase s in plasma corticosterone.