Comparison of the potency of MDL 100,907 and SB 242084 in blocking the serotonin (5-HT)(2) receptor agonist-induced increases in rat serum corticosterone concentrations: evidence for 5-HT(2A) receptor mediation of the HPA axis.
Direct-acting serotonin (5-HT) receptor agonists increase serum corticosterone in rats by activating receptors of the 5-HT(1A) or the 5-HT(2A/2C) subtypes. While involvement of 5-HT(1A) receptors in activation of the hypothalamic-pituitary-adrenocortical (HPA) axis is clear, the 5-HT(2) receptor subtype--5-HT(2A) or 5-HT(2C)--responsible for activation of the HPA axis by direct-acting 5-HT(2) receptor agonists has been difficult to determine due to the lack of selective pharmacologic agents. Recently, however, 5-HT(2) receptor antagonists with high selectivity for 5-HT(2A) and 5-HT(2C) receptor subtypes have been discovered. The selective 5-HT(2A) receptor antagonist MDL 100,907 and the selective 5-HT(2C) receptor antagonist SB 242084 were used to block the increases in rat serum corticosterone elicited by 5-HT(2) receptor agonists with varying degrees of affinity for 5-HT(2A) and 5-HT(2C) receptors. MDL 100,907 was fully effective in blocking the increases in corticosterone concentrations produced by quipazine, DOI, m-CPP and Ro 60-0175, whereas SB 242084 was ineffective or was only marginally effective. Our findings implicate 5-HT(2A) receptors rather than 5-HT(2C) receptors in mediating increases in rat serum corticosterone produced by direct-acting 5-HT(2) receptor agonists in vivo.
Hemrick-Luecke
Susan K
SK
Neuroscience Research Division, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Drop Code 0510, Indianapolis, IN 46285, USA. luecke_susan_h@lilly.com
Evans
David C
DC
D000631:Aminopyridines / Q000494:pharmacology*; D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D003345:Corticosterone / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D005021:Ethylamines / Q000494:pharmacology; D005464:Fluorobenzenes / Q000494:pharmacology*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D011814:Quipazine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
C107820:6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline; D000631:Aminopyridines; D000662:Amphetamines; D005021:Ethylamines; D005464:Fluorobenzenes; D007211:Indoles; D010879:Piperazines; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; C103848:Ro 60-0175; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D011814:Quipazine; C079049:volinanserin; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine; C015068:1-(3-chlorophenyl)piperazine; D003345:Corticosterone