5-Hydroxytryptophan-induced myoclonus in guinea pigs: mediation through 5-HT1/2 receptor subtypes.
In guinea pigs, myoclonus can be induced by 5-hydroxytryptamine (5-HT, serotonin) precursors and synthetic 5-HT receptor agonists, yet the receptor subtype specificity of this behavior is not fully delineated. Guinea pigs were pre-treated with carbidopa (50 mg) followed by one of eight 5-HT antagonists: (-)-N-tert-butyl-3-[4-(2-methoxyphenyl) piperazin-1-yl]-2-phenyl propionamide ((-)-WAY 100135) (5-HT1A), N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-N-(2-pyridyl)-cy clohexancarboxamide (WAY 100635) (5-HT1A), methiothepin mesylate (5-HT1/2), mesulergine hydrochloride (5-HT2A/2C), N[4-methoxy-3-(4-methyl-L-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1,2 ,4-oxadizol-3-yl) (GR 127935) (5-HT1D), trans-4-[(3Z)3-(2-dimethylaminoethyl)oxyimino-3(2-fluorop hen yl) propen-1-yl]phenol, hemifumarate (SR 46349) (5-HT2), ondansetron hydrochloride (5-HT3), and [1-[2-[methylsulphonyl)amino]ethyl]-4-piperidinyl]methyl-5-fluoro-2-meth oxy-1H-indole-3-carboxylate (GR 125487) (5-HT4). Thirty minutes later, they received 5-hydroxytryptophan (5-HTP) (75 mg/kg, sc) and myoclonic jumping rates were assessed every 10 min for 200 min by a blinded observer. Repeated measures analysis of variance of drug-induced antagonism of 5-HTP-induced myoclonus revealed a significant effect for the 5-HT receptor antagonists methiothepin mesylate, GR127935, and mesulergine hydrochloride compared to placebo, and each of these drugs inhibited 5-HTP-induced myoclonus in a dose-dependent fashion. Based on the receptor profiles of the three effective antagonists, 5-HTP-induced myoclonus is influenced by the 5-HT1/2 receptor systems. The absence of a significant change with any other receptor subtype antagonist suggests that myoclonus is not related to diffuse activation of central serotonergic mechanisms.
Pappert
E J
EJ
Rush-Presbyterian-St. Luke's Medical Center, Department of Neurological Sciences, Chicago, IL 60612, USA.
Goetz
C G
CG
Stebbins
G T
GT
Belden
M
M
Carvey
P M
PM
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004873:Ergolines / Q000494:pharmacology; D006168:Guinea Pigs; D008297:Male; D008719:Methiothepin / Q000494:pharmacology; D009207:Myoclonus / Q000139:chemically induced* / Q000188:drug therapy*; D010069:Oxadiazoles / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000145:classification* / Q000187:drug effects / Q000502:physiology; D012701:Serotonin / Q000633:toxicity*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013379:Substrate Specificity
D004873:Ergolines; D010069:Oxadiazoles; D010879:Piperazines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C090701:GR 127935; D012701:Serotonin; D008719:Methiothepin; C031649:mesulergine