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Studies of the brain biochemical analysis and the treatment of schizophrenia

脑生化分析与精神分裂症治疗的研究

基本信息

批准号：
62480243
负责人：
TORU Michio
金额：
$ 4.16万
依托单位：
Tokyo Medical and Dental University (1989)Shinshu University (1987-1988)
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1987
资助国家：
日本
起止时间：
1987 至 1989
项目状态：
已结题

项目摘要

In the analysis of post-mortem brains of 14 chronic schizophrenic patients and 10 controls, we measured the uptake sites of dopamine, benzodiazepine receptors and N-methyl-D-aspartate(NMDA) receptors. Dopamine uptake sites were measured by using ^3-GBR 12935 and a significant increase of specific binding was found in the schizophrenic putamen but not in the caudate. Benzodiazepine receptors, which have never measured in the schizophrenic brain, were analyzed by specific ^3-flunitrazepam binding to 12 brain areas. We found increased specific binding in schizophrenic group to 3 areas of the prefrontal cortex, 2 areas of the temporal cortex and cornu Ammonis. The specific ^3-flunitrazepam binding values positively correlate with GABA contents, the specific ^3-kainate binding values, tyrosine hydroxylase activity, Bmax values of dopamine D2 binding and substance P immunoreactivity while they negatively correlate with glutamic acid contents. ^3-MK801 was used to label the NMDA receptors. Am … More ong 14 brain areas assayed, the specific ^3-MK801 binding was significantly increased in the superior temporal gyrus, the superior parietal cortex and the supra-marginal cortex of schizophrenic patients. The ^3-MK801 binding values positively correlate with ^3-kainate binding values, Bmax values of D2 binding, tyrosine hydroxylase activity, substance P, methionine-enkephalin and CCK-8 immunoreactivity while they negatively correlate with glutamic acid contents.These results suggest that several neuropeptides such as substance P, methionine-enkephalin and CCK-8 function with dopaminergic hyperactivity in the same direction resulting hypofunction of glutamatergic neurons. Subcortical hypoglutamatergic states might induce supersensitivity of glutamate receptors as shown in the increase of ^3-kainate and ^3-MK801 binding. Since these results were obtained from chronic schizophrenic brains, one possibility of developing new drugs to treat chronic states of schizophrenia could be to activate glutamat ergic neurons in the brain. Less

在对14例慢性精神分裂症患者和10例对照者的死后大脑进行分析中，我们测量了多巴胺、苯二氮卓受体和n -甲基- d -天冬氨酸（NMDA）受体的摄取位点。使用^3-GBR 12935测量多巴胺摄取位点，发现在精神分裂症的壳核中特异性结合显著增加，而在尾状核中没有。在精神分裂症患者的大脑中从未测量过的苯二氮受体，通过特定的^3-氟硝西泮与12个大脑区域的结合来分析。我们发现，在精神分裂症组中，前额叶皮层的3个区域、颞叶皮层的2个区域和锥体的特异性结合增加。^3-氟硝西平特异性结合值与GABA含量、^3-海因酸盐特异性结合值、酪氨酸羟化酶活性、多巴胺D2结合Bmax值和P物质免疫反应性呈正相关，与谷氨酸含量呈负相关。^3-MK801用于标记NMDA受体。在14个脑区中，^3-MK801特异性结合在精神分裂症患者的颞上回、顶叶上皮层和边缘上皮层显著增加。^3-MK801结合值与^3-海因酸盐结合值、D2结合Bmax值、酪氨酸羟化酶活性、P物质、蛋氨酸-脑啡肽和CCK-8免疫反应性呈正相关，与谷氨酸含量呈负相关。这些结果表明，多种神经肽如P物质、蛋氨酸-脑啡肽和CCK-8在同一方向上与多巴胺能亢进作用，导致谷氨酸能神经元功能低下。皮层下低谷氨酸能状态可诱导谷氨酸受体的超敏感，表现为^3-kainate和^3-MK801结合的增加。由于这些结果是从慢性精神分裂症患者的大脑中获得的，因此开发治疗慢性精神分裂症的新药的一种可能性是激活大脑中的谷氨酸能神经元。少