Abnormal excitatory neurotransmitter metabolism in schizophrenic brains.
Abnormal excitatory neurotransmitter metabolism in schizophrenic brains.
复制标题
DOI：
10.1001/archpsyc.1995.03950220039008
复制
发表时间：
1995-10
影响因子：
--
通讯作者：
Guochuan Tsai;L. Passani;Barbara S. Slusher;R. E. Carter;Lee Baer;J. Kleinman;Joseph T. Coyle
中科院分区：
文献类型：
--
作者：
Guochuan Tsai;L. Passani;Barbara S. Slusher;R. E. Carter;Lee Baer;J. Kleinman;Joseph T. Coyle
精神分裂症被认为是由谷氨酸能神经元功能低下引起的。精神分裂症患者脑脊液中谷氨酸浓度降低的发现以及谷氨酸受体拮抗剂引起精神病症状的能力支持了这一假设。n -乙酰天冬氨酸（NAAG）是一种高度集中于谷氨酸能神经元的神经肽，可拮抗谷氨酸对n -甲基- d -天冬氨酸受体的影响。此外，NAAG被一种特殊的肽酶——n -乙酰- α连接的酸性二肽酶（NAALADase）裂解成谷氨酸和n -乙酰天冬氨酸。为了验证精神分裂症的谷氨酸能假说，我们研究了精神分裂症患者、接受抗精神病药治疗的对照组和正常人死后大脑中naag相关的谷氨酸能变量，特别强调了前额皮质和海马。方法对三组（精神分裂症患者、接受抗精神病药治疗的对照组和正常对照组）冷冻脑组织的不同区域进行NAAG、n -乙酰天冬氨酸、NAALADase和几种氨基酸（包括天冬氨酸和谷氨酸）水平的测定。结果：我们的研究证实了脑内天冬氨酸、谷氨酸和NAAG水平以及NAALADase活性的改变。精神分裂症患者的NAAG水平升高，NAALADase活性和谷氨酸水平降低。值得注意的是，精神分裂症患者大脑中NAAG水平和NAALADase活性的变化比天冬氨酸和谷氨酸的变化更具选择性。在接受抗精神病药治疗的对照组中，天冬氨酸、谷氨酸和甘氨酸的水平升高。结论：天冬氨酸、谷氨酸、NAAG和NAALADase水平的变化在前额叶和海马区表现突出，此前对精神分裂症大脑的神经病理学研究显示了一致的变化。这些发现支持了精神分裂症是由某些谷氨酸神经系统功能低下引起的假说。他们还认为，抗精神病药的治疗效果可能与谷氨酸活性的增加有关。
BACKGROUND Schizophrenia has been hypothesized to be caused by a hypofunction of glutamatergic neurons. Findings of reduced concentrations of glutamate in the cerebrospinal fluid of patients with schizophrenia and the ability of glutamate-receptor antagonists to cause psychotic symptoms lend support to this hypothesis. N-acetylaspartylglutamate (NAAG), a neuropeptide that is highly concentrated in glutamatergic neurons, antagonizes the effects of glutamate at N-methyl-D-aspartate receptors. Moreover, NAAG is cleaved to glutamate and N-acetylaspartate by a specific peptidase, N-acetyl-alpha-linked acidic dipeptidase (NAALADase). To test the glutamatergic hypothesis of schizophrenia, we studied the NAAG-related glutamatergic variables in postmortem brains from patients with schizophrenia, neuroleptic-treated controls, and normal individuals, with particular emphasis on the prefrontal cortex and hippocampus. METHOD Different regions of frozen brain tissue from three different groups (patients with schizophrenia, neuroleptic-treated controls, and normal controls) were assayed to determine levels of NAAG, N-acetylaspartate, NAALADase, and several amino acids, including aspartate and glutamate. RESULTS Our study demonstrates alterations in brain levels of aspartate, glutamate, and NAAG and in NAALADase activity. Levels of NAAG were increased and NAALADase activity and glutamate levels were decreased in the schizophrenic brains. Notably, the changes in NAAG level and NAALADase activity in schizophrenic brains were more selective than those for aspartate and glutamate. In neuroleptic-treated control brains, levels of aspartate, glutamate, and glycine were found to be increased. CONCLUSIONS The changes in levels of aspartate, glutamate, NAAG, and NAALADase are prominent in the prefrontal and hippocampal regions, where previous neuropathological studies of schizophrenic brains demonstrate consistent changes. These findings support the hypothesis that schizophrenia results from a hypofunction of certain glutamatergic neuronal systems. They also suggest that the therapeutic efficacy of neuroleptics may be related to increased glutamatergic activity.