Fitzgerald L W, Deutch A Y, Gasic G, Heinemann S F, Nestler E J
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06508.
J Neurosci. 1995 Mar;15(3 Pt 2):2453-61. doi: 10.1523/JNEUROSCI.15-03-02453.1995.
Because glutamate is an important modulator of subcortical dopamine (DA) function, and abnormal glutamate/DA interactions may be involved in the pathophysiology of schizophrenia, we examined the effect of chronically administered antipsychotic drugs (APDs) on the levels of specific glutamate receptor subunits in the terminal fields of nigrostriatal and mesocorticolimbic DA systems. By immunoblotting procedures using antibodies specific for the NMDAR1, GluR1, and GluR2 subunits, we found that haloperidol (predominantly a D2-like antagonist) increased NMDAR1 subunit immunoreactivity (and mRNA levels) in the striatum, while the D1-like antagonist SCH 23390 had the opposite effect. No effect was seen on GluR1 or GluR2 levels. The result that D1-like and D2-like receptor antagonism can reciprocally regulate NMDAR1 expression is consistent with our observation that complete unilateral destruction of the nigrostriatal DA pathway with 6-hydroxy-dopamine had no effect on striatal NMDAR1 subunit levels. Further examination of these striatal effects revealed that chronic treatment with the D2-like receptor antagonist raclopride significantly increased NMDAR1 levels in the striatum, while the 5-HT2a/2c antagonist mianserin tended to produce an increase that did not achieve statistical significance. These findings indicate that the dopaminergic antagonist properties of haloperidol are likely most responsible for its regulation of this subunit. In contrast, the atypical APD clozapine had no effect on striatal NMDAR1 levels, consistent with the relatively weaker influence of this drug on nigrostriatal DA function. The second major finding of the present study was the ability of haloperidol and clozapine to increase GluR1 levels in the medial prefrontal cortex (PFC), whereas chronic SCH 23390 treatment decreased GluR1 levels.
由于谷氨酸是皮层下多巴胺（DA）功能的重要调节因子，且谷氨酸/DA相互作用异常可能参与精神分裂症的病理生理学过程，我们研究了长期给予抗精神病药物（APD）对黑质纹状体和中皮质边缘DA系统终末区域特定谷氨酸受体亚基水平的影响。通过使用针对NMDAR1、GluR1和GluR2亚基的特异性抗体的免疫印迹程序，我们发现氟哌啶醇（主要是一种D2样拮抗剂）增加了纹状体中NMDAR1亚基的免疫反应性（和mRNA水平），而D1样拮抗剂SCH 23390则产生相反的效果。对GluR1或GluR2水平未见影响。D1样和D2样受体拮抗作用可相互调节NMDAR1表达的结果与我们的观察一致，即6-羟基多巴胺完全单侧破坏黑质纹状体DA通路对纹状体NMDAR1亚基水平无影响。对这些纹状体效应的进一步研究表明，用D2样受体拮抗剂雷氯必利长期治疗可显著增加纹状体中NMDAR1水平，而5-HT2a/2c拮抗剂米安色林倾向于产生增加，但未达到统计学显著性。这些发现表明，氟哌啶醇的多巴胺能拮抗特性可能是其调节该亚基的主要原因。相比之下，非典型APD氯氮平对纹状体NMDAR1水平无影响，这与该药物对黑质纹状体DA功能的相对较弱影响一致。本研究的第二个主要发现是氟哌啶醇和氯氮平能够增加内侧前额叶皮质（PFC）中的GluR1水平，而长期给予SCH 23390治疗则降低了GluR1水平。
