Role of 5-HT(2) receptors in the tryptamine-induced 5-HT syndrome in rats.
We distinguished the functions of the different 5-hydroxytryptamine-2 (5-HT(2)) receptor (5-HT(2)R) subtypes in the tryptamine-induced 5-HT syndrome in rats using (1) the 5-HT(2A)R antagonist R93274 (N-[(3-p-fluorophenyl-1-propyl)-4-methyl-4-piperidinyl]-4-amino-5-iodo-2-methoxybenzamide), the 5-HT(2A/C)R antagonist R99647 (2-(dimethylaminomethyl)2,3,3a,8-tetrahydrodibenzo[c,f]isoxazolo[2,3-a]azepine), the 5-HT(2B/C)R antagonist SB-242084 (6-chloro-5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-indoline), and several 5-HT(2)R antagonists (ketanserin, risperidone, pipamperone and mianserin); and (2) chronic 5-HT(2)R activation by 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM). In contrast to SB-242084, the selective 5-HT(2A)R antagonist R93274 as well as the non-selective 5-HT(2A)R antagonists (R99647, ketanserin, risperidone, pipamperone and mianserin) significantly inhibited tryptamine-induced forepaw treading and tremors, and reversed peripherally mediated cyanosis into hyperaemia; only the 5-HT(2A/C)R antagonists R99647 and mianserin inhibited the tryptamine-induced hunched back. Intermittent DOM administration (intravenously every 48 h for 12 days) did not change the centrally mediated tryptamine-induced forepaw treading, tremors and hunched back at 1, 4 or 7 days after the last DOM pretreatment. The DOM-induced head twitch response, measured immediately after every DOM injection, was not affected. In contrast, peripherally mediated cyanosis was reversed into hyperaemia in 75, 11 and 20% of all pretreated rats at 1, 4 and 7 days, respectively, after the last DOM administration. Taken together, these finding suggest that central 5-HT(2A)Rs mediate tryptamine-induced forepaw treading and tremors, that peripheral 5-HT Rs mediate tryptamine-induced cyanosis, and that 5-HT(2A)Rs mediate tryptamine-induced hunched back. Peripheral 5-HT(2C)Rs are more sensitive to desensitization after intermittent treatment with an agonist than central 5-HT(2A)Rs.
Van Oekelen
D
D
Discovery Research, Janssen Research Foundation, Beerse, Belgium.
Megens
A
A
Meert
T
T
Luyten
W H M L
WH
Leysen
J E
JE
D004290:DOM 2,5-Dimethoxy-4-Methylamphetamine / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D020230:Serotonin Syndrome / Q000139:chemically induced / Q000378:metabolism*; D014363:Tryptamines
D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; D004290:DOM 2,5-Dimethoxy-4-Methylamphetamine; C030820:tryptamine