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Vickers SP, Easton N, Malcolm CS, Allen NH, Porter RH, Bickerdike MJ, Kennett GA: Modulation of 5-HT (2A) receptor-mediated head-twitch behaviour in the rat by 5-HT (2C) receptor agonists. Pharmacol Biochem Behav. 2001 Jul-Aug;69(3-4):643-52.
The pharmacology of several commonly described 5-hydroxytryptamine (5-HT)(2C) receptor agonists was investigated in vivo and in vitro at rat 5-HT (2A), 5-HT (2B), and 5-HT (2C) receptors. The 5-HT (2C) 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-HT (2C) receptor 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-HT (2A) receptor antagonists R (+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl-ethyl)]-4-piperidine -methanol (MDL 100907) or ketanserin. The preferential 5-HT (2C) receptor agonists Ro 60-0175, 6-chloro-2-[1-piperazinyl]-pyrazine HCl (MK-212), 1-(3-chlorophenyl) piperazine hydrochloride (mCPP), 1-(3-trifluoromethylphenyl) piperazine hydrochloride (TFMPP), and (S)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl) oxy]-pyrollidine HCl (ORG-37684), the 5-HT (2A/2C) receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI), the 5-HT (2B) receptor agonist 1-[5-thienylmethoxy-1-1H-3-indoyl] propan-2-amine hydrochloride (BW-723C86), and nor-D-fenfluramine were 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-HT (2) receptors using a fluorometric imaging plate reader (FLIPR). Both the in vivo and in vitro data suggest that for some ligands, previous reports have overestimated their in vivo selectivity for the 5-HT (2C) receptor. |
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