Head and whole-body jerking in guinea pigs are differentially modulated by 5-HT1A, 5-HT1B/1D and 5-HT2A receptor antagonists.
The present study examined the role of 5-hydroxytryptamine 5-HT receptor subtypes on 5-hydroxytryptamine- (5-HT-) mediated myoclonus in guinea pigs, evaluating head and whole-body jerking as two distinct behavioural responses. Myoclonus was induced by the 5-HT precursor L-5-hydroxytryptophan (L-5-HTP) and the non-selective 5-HT1A/1B/5-HT2 receptor agonist 5-methoxy-N,N-dimethyl-tryptamine (5-MeODMT). The selective 5-HT1A receptor antagonist WAY100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cycloh exanecarboxamide trihydrochloride) inhibited both head and whole-body jerking. The selective 5-HT1B/1D receptor antagonist GR127935 (N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1 ,2,4-oxadiazol-3-yl)[1,1'-biphenyl]-4-carboxamide hemifumarate) only inhibited whole-body jerking, which resulted in unmasked head jerking. Co-administration of GR127935 and the selective 5-HT2A receptor antagonist MDL100.151 ((+/-)-alpha-(2,3-dimethoxyphenyl)-1-[-2-(4-fluorphenyl)ethyl]-4-+ ++piperidinmethanol) caused a complete inhibition of whole-body as well as head jerking. MDL100.151 had only limited effect on myoclonic jerking when given alone. The inhibitory effects of the 5-HT receptor antagonists on either L-5-HTP- or 5-MeODMT-induced myoclonus were found to be very similar. These data confirm a role for the 5-HT1A and 5-HT1B/1D receptors and suggest a role for 5-HT2A receptors in mediating myoclonus in guinea pigs. Moreover, the study shows that by considering head and whole-body jerking as two pharmacologically distinct behavioural responses, subtype specific 5-HT1A, 5-HT1B/1D and 5-HT2A receptor antagonists can be distinguished.
Nielsen
C K
CK
Pharmacological Research, H. Lundbeck A/S, Copenhagen, Denmark. ckn@lundbeck.com
D006916:5-Hydroxytryptophan; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D006168:Guinea Pigs; D019416:Head Movements / Q000187:drug effects*; D008297:Male; D008732:Methoxydimethyltryptamines; D009207:Myoclonus / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D010069:Oxadiazoles / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000494:pharmacology / Q000627:therapeutic use*
D001552:Benzazepines; C115236:MDL 100,151; D008732:Methoxydimethyltryptamines; D010069:Oxadiazoles; D010879:Piperazines; D011725:Pyridines; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; C090701:GR 127935; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D006916:5-Hydroxytryptophan