Modulation of 5-HT2A receptor-mediated head-twitch behaviour in the rat by5-HT2C receptor agonists

The pharmacology of several commonly described 5-hydroxytryptamine (5-HT)(2 C) receptor agonists was investigated in vivo and in vitro at rat 5-HT2A, 5 -HT2B, and 5-HT2C receptors. The 5-HT2C receptor agonist, (S)-2-(6-chloro-5 -fluoroindol-1-yl)-1-methylethylamine fumarate (Ro 60-0175), did not induce a significant head-twitch response when given alone, yet when administered to rats subsequent to an acute challenge with the selective 5-HT2C recepto r antagonist, 6-chloro-5-methyl-1-[6-(2-methylpyridin-3-yloxy) pyridin-3-yl carbomyl] indoline (SB-242084), a robust head-twitch response was observed which was blocked by the selective 5-HT2A receptor antagonists R(+)-alpha- (2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl-ethyl)]-4-piperidine-methanol ( ML 100907) or ketanserin. The preferential 5-HT2C receptor agonists Ro 60-0 175, 6-chloro-2-[1-piperazinyl]-pyrazine HCl (MK-212), 1-(3-chlorophenyl)pi perazine hydrochloride (mCPP), 1-(3-trifluoromethylphenyl)piperazine hydroc hloride (TFMPP), and (S)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy]-pyrol lidine HCl (ORG-37684), the 5-HT2A/2C receptor agonist 2,5-dimethoxy-4-iodo amphetamine (DOI), the 5-HT2B receptor agonist 1-[5-thienylnethoxy-1-1H-3-i ndoyl] propan-2-amine hydrochloride (BW-723C86), and nor-D-fenfluramine wer e administered to rats subsequent to an acute challenge of SB-242084. Under such conditions, each agonist, with the exception of BW-723C86, induced a dose-dependent increase in the incidence of head-twitches. The pharmacology of the same agonists was determined at cloned rat 5-HT2 receptors using a fluorometric imaging plate reader (FLIPR). Both the in vivo and in vitro da ta suggest that for some ligands, previous reports have overestimated their in vivo selectivity for the 5-HT2C receptor. (C) 2001 Elsevier Science Inc . All rights reserved.