Inhibition by sigma receptor ligand, MS-377, of N-methyl-D-aspartate-induced currents in dopamine neurons of the rat ventral tegmental area
Inhibition by sigma receptor ligand, MS-377, of N-methyl-D-aspartate-induced currents in dopamine neurons of the rat ventral tegmental area
复制标题
西格玛受体配体 MS-377 对大鼠腹侧被盖区多巴胺神经元 N-甲基-D-天冬氨酸诱导电流的抑制
作者：
Y. Yamazaki;Miwa Ishioka;H. Matsubayashi;T. Amano;M. Sasa
结论：MS-377NMDA四氢吡喃-1-基]甲基-2-吡咯烷酮L酒石酸酯是一种新型抗精神病候选药物，对[(R)-(+)-1-(4-chlorophenyl)-3-[4-(2-methoxyethyl)受体/离子通道复合体的PCP结合部位缺乏亲和力，但对Sigma受体具有高亲和力。目的：研究MS-377对NMDA受体和/或其离子通道复合体的影响，以阐明MS-377的抗精神病作用。方法：采用膜片钳全细胞记录技术，观察MS-377对急性分离的大鼠腹侧被盖区(VTA)多巴胺神经元N-甲基-D-天冬氨酸(NMDA)诱发电流的影响。结果：浴液中加入MS-377可浓度依赖性地抑制N-甲基-D-天冬氨酸诱发的峰值电流，作用2小时后呈剂量依赖性。其他Sigma受体配体BD-1063、(1-[2-(3，4-dichlorophenyl)ethyl]-4-methylpiperazine)，NE-100(N，N-dipropyl-2-[4-methoxy-3-(2-phenylenoxy)-phenyl]-ethylamine一盐酸盐)和氟哌啶醇也以浓度依赖的方式抑制NMDA性电流。有趣的是，MS-377与BD-1063、NE-100或氟哌啶醇在不影响NMDA诱导电流的浓度下同时使用，增强了MS-377诱导的抑制作用。结论：MS-377与其他Sigma受体配体一样，间接作用于Sigma受体，抑制VTA多巴胺神经元NMDA受体/离子通道复合体介导的谷氨酸能传递，从而抑制VTA靶区多巴胺的释放。
Abstract.Rationale: MS-377 [(R)-(+)-1-(4-chlorophenyl)-3-[4-(2-methoxyethyl) piperazin-1-yl]methyl-2-pyrrolidinone L-tartate] 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. Objectives: 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.
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DOI：
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发表时间：
1992-11
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
H. Ujihara;E. Albuquerque
通讯作者：
H. Ujihara;E. Albuquerque
影响因子：
3.6
作者：
Liao, GY;Wagner, DA;Leonard, JP
通讯作者：
Leonard, JP
Sigma 受体负向调节大鼠脑中激动剂刺激的磷酸肌醇代谢。
影响因子：
5
作者：
Bowen,WD;Kirschner,BN;Newman,AH;Rice,KC
通讯作者：
Rice,KC
苯环己哌啶类似物的开放通道阻断和 N-甲基-D-天冬氨酸受体门控的改变。
影响因子：
3.4
作者：
Dilmore,JG;Johnson,JW
通讯作者：
Johnson,JW
抗精神病药与人脑受体的结合：与临床效果的关系。
影响因子：
5.2
作者：
Richelson,E
通讯作者：
Richelson,E