Ž . European Journal of Pharmacology 347 1998 51–56 5-Hydroxytryptophan-induced myoclonus in guinea pigs: mediation through 5-HT receptor subtypes 1r2 Eric J. Pappert ) , Christopher G. Goetz, Glenn T. Stebbins, Matt Belden, Paul M. Carvey Rush-Presbyterian-St. Luke’s Medical Center, MoÕement Disorders Section, Department of Neurological Sciences, 1725 W. Harrison AÕe., Suite 1106, Chicago, IL 60612, USA Received 1 December 1997; accepted 27 January 1998 Abstract Ž . In guinea pigs, myoclonus can be induced by 5-hydroxytryptamine 5-HT, serotonin precursors and synthetic 5-HT receptor agonists, Ž . yet the receptor subtype specificity of this behavior is not fully delineated. Guinea pigs were pre-treated with carbidopa 50 mg followed Ž . w Ž . x ŽŽ . . by one of eight 5-HT antagonists: y -N-tert-butyl-3- 4- 2-methoxyphenyl piperazin-1-yl -2-phenyl propionamide y -WAY 100135 Ž . w w Ž . x x Ž . Ž .Ž . 5-HT , N- 2- 4- 2-methoxypheny -1-piperazinyl -ethyl -N- 2-pyridyl -cyclohexancarboxamide WAY 100635 5-HT , methiothepin 1A 1A Ž . Ž . w Ž . x X X Ž mesylate 5-HT , mesulergine hydrochloride 5-HT , N 4-methoxy-3- 4-methyl-L-piperazinyl phenyl -2 -methyl-4 - 5-methyl- 1r2 2Ar2C . Ž . Ž . wŽ . Ž . Ž . x 1,2,4-oxadizol-3-yl GR 127935 5-HT , trans-4- 3 Z 3- 2-dimethylaminoethyl oxyimino-3 2-fluorophenyl propen-1-yl phenol, 1D Ž .Ž . Ž . w w w . x x x hemifumarate SR 46349 5-HT , ondansetron hydrochloride 5-HT , and 1- 2- methylsulphonyl amino ethyl -4-piperidinyl methyl-5- 2 3 Ž .Ž . Ž .Ž fluoro-2-methoxy-1 H-indole-3-carboylate GR 125487 5-HT . Thirty minutes later, they received 5-hydroxytryptophan 5-HTP 75 4 . mgrkg, 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-in- duced 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-HT receptor systems. The absence of a significant change with any other receptor subtype antagonist 1r2 suggests that myoclonus is not related to diffuse activation of central serotonergic mechanisms. q 1998 Elsevier Science B.V. Ž . Ž . Keywords: Myoclonus; Guinea pig ; 5-HT 5-hydroxytryptamine, serotonin ; 5-Hydroxytryptophan 1. Introduction Clinical observations and pharmacological studies sug- Ž gest abnormalities in the serotonin 5-hydroxytryptamine, . Ž 5-HT system in some forms of human myoclonus Bris- saud and Beauvais, 1969; Dyken and Kola, 1968; Solomon . and Chutorian, 1968 . Specifically, in post-hypoxic my- Ž .Ž oclonus Lance–Adams syndrome Lance and Adams, . 1963 , multiple studies including cerebrospinal fluid analy- ses and clinical trials suggest a specific link to 5-HT Ž . pharmacology Lhermitte et al., 1972; Thal et al., 1980 . In guinea pigs, generalized myoclonic jumping behavior can be induced by the subcutaneous injection of 5- Ž . hydroxytryptophan 5-HTP , the immediate precursor to Ž . 5-HT Klawans et al., 1973 . This behavior is abolished by ) Corresponding author. Tel.: q1-312-942-4500; fax: q1-312-942- 2380. the acute administration of methysergide, a non-specific Ž . serotonergic antagonist Goetz and Klawans, 1974 . In- tracisternal injections of 5,7-dihydroxytryptamine or chronic treatment with non-specific 5-HT receptor antago- nists induces supersensitivity to this myoclonic response Ž . Klawans et al., 1975; Pranzatelli and Snodgrass, 1987 . In the last decade, numerous 5-HT receptor subtypes have been identified and are heterogeneously distributed Ž throughout the nervous system Gozlan et al., 1983; Hartig et al., 1996; Heuring and Peroutka, 1987; Hoyer et al., 1988, 1994; Leonhardt et al., 1989; Leysen et al., 1982; . Ž . Peroutka, 1986 . Pranzatelli et al. 1993b demonstrated that the guinea pig brain stem contained all of the 5-HT 1 receptor binding sites, as well as agonist- and antagonist- labeled 5-HT sites and 5-HT uptakertransporter sites. In 2 this animal, serotonin receptor binding site density rank order is: 5-HT ) antagonist-labeled 5-HT ) 5-HT and 1D 2 1A Ž 5-HT ) 5-HT ) agonist-labeled 5-HT Pranzatelli et 2C 1E 2 . al., 1993b . 0014-2999r98r$19.00 q 1998 Elsevier Science B.V. All rights reserved.