Inhibition by sigma receptor ligand, MS-377, of N-methyl- D-aspartate-induced currents in dopamine neurons of the rat ventral tegmental area.
BACKGROUND
MS-377 [( R)-(+)-1-(4-chlorophenyl)-3-[4-(2-methoxyethyl) piperazin-1-yl]methyl-2-pyrrolidinone L-tartrate] is a novel anti-psychotic drug candidate with high affinity for sigma receptors but devoid of binding affinity for PCP binding site of NMDA receptor/ion channel complex.


OBJECTIVE
The effects of MS-377 on NMDA receptor and/or its ion channel complex were examined to elucidate the antipsychotic properties of MS-377.


METHODS
We examined the effect of MS-377 on NMDA ( N-methyl- D-aspartate)-induced current in acutely dissociated dopamine neurons of rat ventral tegmental area (VTA) using patch clamp whole cell recording.


RESULTS
MS-377 applied in a bath inhibited the peak current evoked by NMDA applied via the U-tube method for 2 s in a concentration-dependent manner. Other sigma receptor ligands, BD-1063 (1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine), NE-100 ( N, N-dipropyl-2-[4-methoxy-3-(2-phenylenoxy)-phenyl]-ethylamine monohydrochloride) and haloperidol also inhibited NMDA-induced current in a concentration-dependent manner. Interestingly, concomitant application of MS-377 with BD-1063, NE-100 or haloperidol at concentrations that had no effects on NMDA-induced current, potentiated the MS-377-induced inhibition.


CONCLUSIONS
The results suggest that MS-377, as well as other sigma receptor ligands, indirectly acts on the sigma receptor to inhibit glutaminergic transmission mediated by NMDA receptor/ion channel complex in VTA dopamine neurons, thereby inhibiting dopamine release in target VTA areas.
Yamazaki
Yuu
Y
Department of Pharmacology, Hiroshima University School of Medicine, 1-2-3 Kasumi, Minami-ku, 734-8551, Japan.
Ishioka
Miwa
M
Matsubayashi
Hiroaki
H
Amano
Taku
T
Sasa
Masashi
M
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D017480:Receptors, sigma / Q000187:drug effects* / Q000502:physiology; D013644:Tartrates / Q000494:pharmacology*; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000502:physiology
C464615:1-(4-chlorophenyl)-3-(4-(2-methoxyethyl) piperazin-1-yl)methyl-2-pyrrolidinone tartrate; D014150:Antipsychotic Agents; D011759:Pyrrolidines; D016194:Receptors, N-Methyl-D-Aspartate; D017480:Receptors, sigma; D013644:Tartrates; D016202:N-Methylaspartate