Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to antipsychotics for the treatment of schizophrenia.

BACKGROUND: Hypofunction of N-methyl-D-aspartate glutamate receptor had been implicated in the pathophysiology of schizophrenia. Treatment with D-serine or glycine, endogenous full agonists of the glycine site of N-methyl-D-aspartate receptor, or D-cycloserine, a partial agonist, improve the symptoms of schizophrenia. N-methylglycine (sarcosine) is an endogenous antagonist of glycine transporter-1, which potentiates glycine's action on N-methyl-D-aspartate glycine site and can have beneficial effects on schizophrenia. METHODS: Thirty-eight schizophrenic patients were enrolled in a 6-week double-blind, placebo-controlled trial of sarcosine (2 g/d), which was added to their stable antipsychotic regimens. Twenty of them received risperidone. Measures of clinical efficacy and side effects were determined every other week. RESULTS: Patient who received sarcosine treatment revealed significant improvements in their positive, negative, cognitive, and general psychiatric symptoms. Similar therapeutic effects were observed when only risperidone-treated patients were analyzed. Sarcosine was well-tolerated, and no significant side effect was noted. CONCLUSIONS: Sarcosine treatment can benefit schizophrenic patients treated by antipsychotics including risperidone. The significant improvement with the sarcosine further supports the hypothesis of N-methyl-D-aspartate receptor hypofunction in schizophrenia. Glycine transporter-1 is a novel target for the pharmacotherapy to enhance N-methyl-D-aspartate function.     

Extracellular adenosine,formed during low level NMDA receptor activation,provides an inhibitory threshold against further NMDA receptor-midiated neurotransmission in the cortex

In the cortex only a few of the available NMDA receptors must be activated to evoke maximal release of adenosine. In fact, maximal adenosine release occurs at 30 μM NMDA, a concentration at which noradrenaline release is only 20% maximal. NMDA-evoked noradrenaline release appears to require the generation of propagated action potentials, while adenosine release does not. Noncompetitive block of NMDA-evoked release of adenosine, but not noradrenaline, can be overcome by increasing NMDA concentrations. The above findings are consistent with the possibility that there are spare receptors for NMDA-evoked adenosine release, but not for nor-adrenaline release. These spare receptors are not due to elevated levels of glycine in the vicinity of those NMDA receptors mediating adenosine release. Functionally, it appears that low level NMDA receptor activation provides a purinergic inhibitory threshold against higher level NMDA receptor mediated processes. This could provide inhibitory tone and selectivity for critical functions, such as learning, memory, and synaptic plasticity in the cortex. © 1993 Wiley-Liss, Inc.     

Autoradiographic localization of dopamine uptake sites in the rat brain with3H-GBR 12935

Summary The firing rate and terminal excitability of identified nigrostriatal dopamine (DA) neurons was determined before, and over a 10–15 min period following, direct intrastriatal administration of the glutamate (GLU) agonist NMDA, or saline. NMDA (0.025 and 0.075 mol) produced a short latency increase in DA cell firing rate. In 7/8 cases, this increase in firing rate was accompanied by a profound reduction in terminal excitability. The decrease in excitability usually outlasted the increase in firing rate (sometimes by more than 8 min), and was superseded at a later stage by a marked increase in excitability. None of these effects were seen with saline (n=5), and they could all be blocked by preadministration of the competitive NMDA antagonist AP-7 (0.025 mol; n=6). The sequence of events leading to the observed results is argued to be as follows; NMDA initially excites striatal efferents to the DA cell, which through disinhibition and direct stimulation increase DA cell firing rate. Increased firing rate leads to enhanced striatal DA release. Dopamine's inhibitory influence pre-empts any effect NMDA itself may have on the terminals of nigrostriatal neurons, and counteracts NMDA's stimulatory effect on striatal output cells. Furthermore, the marked reduction in terminal excitability suggests that DA becomes the dominant influence in the striatum for a time. Hence, the net outcome of the injection is augmented striatal DA tone. Later, the effect of residual NMDA becomes predominant once more.     

Effect of N-phthalamoyl-L-glutamic acid,a selective NMDA receptor agonist,on binding of3H-L-glutamate with hippocampal synaptic membranes

Institute of Experimental Medicine, Russian Academy of Medical Sciences, St. Petersburg. (Presented by Academician of the Russian Academy of Medical Sciences A. N. Klimov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 113, No. 6, pp. 563–565, June, 1992.     

LTP的钙离子通道机制:VDCC LTP和NMDA LTP

长时程增强(LTP)与学习记忆机制关系密切.长时程增强的产生依赖于钙离子通道的活动特性,Ca2+经不同的钙离子通道内流引发的长时程增强对应不同的记忆作用.综述了通过N-甲基-D-天门冬氨酸(NMDA)受体钙离子通道和电压依赖性钙离子通道(VDCC)活动产生LTP及其各自对应的记忆作用,还介绍了以低频刺激方式产生长时程增强的研究实例.     

Cerebral protection by AMPA- and NMDA-receptor antagonists administered after severe insulin-induced hypoglycemia

Summary Excitatory amino acids are implicated in the development of neuronal cell damage following periods of reversible cerebral ischemia or insulin-induced hypoglycemic coma. To explore the importance of glutamate receptor activation in the posthypoglycemic phase, we exposed rats to 20 min of insulin-induced severe hypoglycemia. The rats were treated immediately after the hypoglycemic insult with four regimes of glutamate receptor antagonists: (1) the AMPA (-amino-3-hydroxy-5-methyl-4-isoxazole propriate)-receptor antagonist NBQX [2.3-dihydroxy-6-nitro-7-sulfamoyl-benzo (F) quinoxaline] given as a bolus dose of 30 mg · kg^-1 i.p., followed by an i.v. infusion of 225 g · kg^-1 · min^-1 for 6 h; (2) the non-competitive NMDA-receptor antagonist, dizocilpine (MK-801) 1 mg · kg^-1 given i.v.; (3) a combined NBQX treatment, (a bolus dose of 10 mg · kg^-1 i.p., followed by an i.v. infusion of 225 g · kg^-1 · min^-1 for 6 h), with dizocilpine 0.33 mg · kg^-1 given twice i.p. at 0 and 15 min after recovery and (4) the competitive NMDA-receptor blocker CGP 40116 [D-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid] 10 mg · kg^-1 given i.p.. In the striatum, all glutamate receptor blockers significantly decreased neuronal damage by approximately 30%. An approximately 50% decrease in neuronal damage was demonstrated in neocortex and hippocampus following the combined treatment with NBQX and dizocilpine, while protection was variable following the treatment with a single glutamate-receptor antagonist. We conclude that neuronal damage continues to develop in the striatum and in cortical brain regions in the posthypoglycemic period and that both NMDA- and AMPA-receptors contribute to this process, possibly by a change in the cellular response to both AMPA- and NMDA-receptor stimulation.     

N-甲基-D-天冬氨酸受体拮抗剂类药物在脑缺血损伤中的应用进展

综述了近年来N-甲基-D-天冬氨酸受体拮抗剂治疗脑缺血的应用进展，并从不同作用位点分别对各类药物特点作了阐述。     

镇痛药研究进展

镇痛药研究引入了细胞及分子生物学的最新研究手段和方法，并从神经激肽类阻滞剂、N-甲基-D-天门冬氨酸(N—methyl—D—aspartate，NMDA)受体阻滞剂、腺苷激酶抑制剂、脑啡肽分解酶抑制剂、降钙素基因相关肽(Calcitonin gene—related peptide，CGRP)受体阻滞剂、镇痛复合制剂等方面拓宽了镇痛药研究的思路。新建立的研究模型包括培养脊髓背根神经节神经元模型及吞咽反应模型。     

人参皂苷Rg2对脑缺血再灌注大鼠学习记忆及海马神经元Glu和NMDA受体亚单位表达的影响

目的观察全脑缺血再灌注对大鼠空间学习记忆和海马神经元Glu、N-甲基-D-天冬氨酸受体(NMDAR)亚单位NR1、NR2B表达的影响,探讨人参皂苷Rg2的干预作用。方法SD大鼠56只,采用四血管阻断法制备大鼠全脑缺血再灌注模型(假手术组除外),随机分为7组(各8只):假手术组、模型组、溶酶组(注射2.5 mL/kg的1,2-丙二醇和聚乙二醇400混合液)、人参皂苷Rg2高剂量组(注射10.0 mg/kg人参皂苷Rg2)、中剂量组(注射5.0 mg/kg人参皂苷Rg2)、低剂量组(注射2.5 mg/kg人参皂苷Rg2)、尼莫地平组(注射50μg/kg尼莫地平),MORRIS水迷宫试验检测大鼠学习记忆能力的改变,免疫组织化学和图像分析方法观察Glu、NR1、NR2免疫阳性神经元的表达。结果缺血再灌注模型组大鼠海马Glu、NR1、NR2B免疫阳性神经元的表达与假手术组比较明显增加,人参皂苷Rg2高剂量组Glu、NR1、NR2B神经元的表达与模型组比较明显降低,差异均有显著意义(F=155.249~268.228,q=2.934~5.259,P<0.01)。人参皂苷Rg2高剂量组大鼠逃避潜伏期较模型组明显缩短(F=22.063,q=4.59,P<0.01)。结论人参皂苷Rg2能降低Glu、NR1、NR2B在脑缺血再灌注损伤大鼠海马神经元的表达,并改善学习记忆能力。     

二苯乙烯苷对脑缺血再灌注沙土鼠学习记忆功能及NMDA受体亲合力的影响

目的:研究2,3,5,4'-四羟基二苯乙烯-2-O-β-D-葡萄糖苷(2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside,简称二苯乙烯苷)对脑缺血再灌注沙土鼠学习记忆功能和对N-甲基-D-天冬氨酸(NMDA)受体亲合力的影响.方法:夹闭沙土鼠双侧颈总动脉10min,然后撤去动脉夹实现再灌注,7d后通过水迷宫测定学习记忆功能的改变,随后处死,测定前脑组织NMDA受体与[3H]MK801的亲合力.结果:Morris水迷宫实验显示,模型组游出时间和游泳距离比假手术组明显延长,二苯乙烯苷治疗组的游出时间和游泳距离均比模型组缩短.受体亲合情况测定结果显示,模型组的NMDA受体与[3H]MK801的亲和力比假手术组明显升高,而二苯乙烯苷治疗组可以降低模型动物的NMDA受体亲合力.结论:二苯乙烯苷能够改善缺血再灌注所导致的学习记忆功能障碍,降低NMDA受体与[3H]MK801亲合力,可能具有脑保护作用.