title: Effects of a novel, selective, sigma1-ligand, MS-377, on phencyclidine-induced behaviour.
abstract: Phencyclidine (PCP)-induced head-weaving is inhibited by a novel selective sigma1-ligand, (R)-(+)-1-(4-chlorophenyl)-3-[4-(2-methoxyethyl)piperazin-1-yl]methyl-2-pyrrolidinone L-tartrate (MS-377), but not by dopamine D2 antagonists. In the present study, we examined the effects of two potent and selective sigma1-ligands, MS-377 and N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl) ethylamine (NE-100), on PCP-induced rearing behaviour, hyperlocomotion and ataxia in comparison with the currently available antipsychotic agents with affinity for D2 receptors, haloperidol, sultopride and risperidone. Male Wistar rats or ddY mice were administered MS-377, NE-100, haloperidol, sultopride or risperidone, and PCP was administered 60 min later (in the case of NE-100 10 min later). Rearing behaviour, hyperlocomotion and ataxia were examined 10 min after PCP administration. MS-377, haloperidol, sultopride and risperidone dose-dependently inhibited PCP-induced rearing and hyperlocomotion, but did not antagonize PCP-induced ataxia. In contrast, the other selective sigma1-ligand, NE-100, did not affect any of the PCP-induced behaviour patterns in this study. These results suggest that there are at least two types of ligands for sigma1-receptors and that some sigma1-ligands, including MS-377, have more comprehensive effects against PCP-induced abnormal behaviour than other sigma1-ligands or D2 antagonists.
authors.affiliation: Drug Discovery Institute, Nihon Schering K.K., Chiba, Japan. shinjitakahashi@schering.co.jp
authors.forename: S
authors.initials: S
authors.lastname: Takahashi
authors.forename: K
authors.initials: K
authors.lastname: Takagi
authors.forename: K
authors.initials: K
authors.lastname: Horikomi
mesh_terms: D000818:Animals; D000840:Anisoles / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001259:Ataxia; D001522:Behavior, Animal / Q000187:drug effects*; D018492:Dopamine Antagonists / Q000494:pharmacology; D006213:Hallucinogens / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008024:Ligands; D008297:Male; D051379:Mice; D023421:Models, Animal; D010622:Phencyclidine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011437:Propylamines / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D017480:Receptors, sigma / Q000378:metabolism*; D013644:Tartrates
chemical_list: C464615:1-(4-chlorophenyl)-3-(4-(2-methoxyethyl) piperazin-1-yl)methyl-2-pyrrolidinone tartrate; D000840:Anisoles; D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D006213:Hallucinogens; D008024:Ligands; D010879:Piperazines; D011437:Propylamines; D011759:Pyrrolidines; D017448:Receptors, Dopamine D2; D017480:Receptors, sigma; D013644:Tartrates; C083832:N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride; D010622:Phencyclidine