title: Effects of sigma(1) receptor ligand MS-377 on D(2) antagonists-induced behaviors.
abstract: (R)-(+)-1-(4-Chlorophenyl)-3-[4-(2-methoxyethyl)piperazin-1-yl]methyl-2-pyrrolidinone L-tartrate (MS-377) is a novel antipsychotic agent with selective and high affinity for sigma(1) receptor. The present study was carried out to clarify the interaction of MS-377 with dopamine D(2) receptor antagonists (D(2) antagonists) in concurrent administration, and then the involvement of sigma receptors in the interaction. The effects of MS-377 on haloperidol- or sultopride-induced inhibition of apomorphine-induced climbing behavior and catalepsy were investigated in mice and rats, respectively. In addition, the effects of (+)-SKF-10,047 and SA4503, both of which are sigma receptor agonists, and WAY-100,635, which is a 5-HT(1A) receptor antagonist, on the interaction due to the concurrent use were also investigated. MS-377 potentiated the inhibitory effects of haloperidol or sultopride on apomorphine-induced climbing behavior in a dose-dependent manner. In contrast, MS-377 did not affect the catalepsy induction by these drugs. The potentiation of the inhibitory effects of haloperidol or sultopride on apomorphine-induced climbing behavior by MS-377 was not inhibited by WAY-100,635, but was inhibited by (+)-SKF-10,047 and SA4503. These findings showed that MS-377 potentiates the efficacy of D(2) antagonists, but it does not deteriorate the adverse effect. Moreover, sigma(1) receptors are involved in this potentiation of the efficacy of D(2) antagonists by MS-377.
authors.affiliation: Drug Discovery Institute, Nihon Schering K.K., 1900-1 Togo, Mobara, Chiba 297-0017, Japan. jkarasawa@schering.co.jp
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Karasawa
authors.forename: Shinji
authors.initials: S
authors.lastname: Takahashi
authors.forename: Kaori
authors.initials: K
authors.lastname: Takagi
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Horikomi
mesh_terms: D000077582:Amisulpride; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001058:Apomorphine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D002375:Catalepsy / Q000139:chemically induced / Q000523:psychology; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D004347:Drug Interactions; D005260:Female; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D051379:Mice; D018697:Nootropic Agents / Q000494:pharmacology; D010620:Phenazocine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017480:Receptors, sigma / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013469:Sulpiride / Q000031:analogs & derivatives* / Q000494:pharmacology; D013644:Tartrates / Q000494:pharmacology*; D000097605:Sigma-1 Receptor
chemical_list: D000077582:Amisulpride; D014150:Antipsychotic Agents; D001058:Apomorphine; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D006220:Haloperidol; D018697:Nootropic Agents; D010620:Phenazocine; D010879:Piperazines; D011725:Pyridines; D011759:Pyrrolidines; D017480:Receptors, sigma; D012702:Serotonin Antagonists; D013469:Sulpiride; D013644:Tartrates; D000097605:Sigma-1 Receptor; C464615:1-(4-chlorophenyl)-3-(4-(2-methoxyethyl) piperazin-1-yl)methyl-2-pyrrolidinone tartrate; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; C012134:SK&F 10047; C101789:SA 4503