Olney J W, Farber N B
Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
Arch Gen Psychiatry. 1995 Dec;52(12):998-1007. doi: 10.1001/archpsyc.1995.03950240016004.
In this article, we advance a unified hypothesis pertaining to combined dysfunction of dopamine and N-methyl-D-aspartate glutamate receptors that highlights N-methyl-D-aspartate receptor hypofunction as a key mechanism that can help explain major clinical and pathophysiological aspects of schizophrenia. The following fundamental features of schizophrenia are accommodated by this hypothesis: (1) the occurrence of structural brain changes during early development that have the potential for producing subsequent clinical manifestations of schizophrenia, (2) a quiescent period in infancy and adolescence before clinical manifestations are expressed, (3) onset in early adulthood of psychotic symptoms, (4) involvement of dopamine (D2) receptors in some cases but not others that would explain why some but not all patients are responsive to typical neuroleptic therapy, and (5) ongoing neurodegenerative changes and cognitive deterioration in some patients. We propose that since N-methyl-D-aspartate receptor hypofunction can cause psychosis in humans and corticolimbic neurodegenerative changes in the rat brain, and since these changes are prevented by certain antipsychotic drugs, including atypical neuroleptic agents (clozapine, olanzapine, fluperlapine), a better understanding of the N-methyl-D-aspartate receptor hypofunction mechanism and ways of preventing its neurodegenerative consequences in the rat brain may lead to improved pharmacotherapy in schizophrenia.
在本文中，我们提出了一个关于多巴胺与N-甲基-D-天冬氨酸型谷氨酸受体联合功能障碍的统一假说，该假说强调N-甲基-D-天冬氨酸受体功能低下是一个关键机制，有助于解释精神分裂症的主要临床和病理生理学方面。该假说涵盖了精神分裂症的以下基本特征：（1）在早期发育过程中发生的大脑结构变化，这些变化有可能产生精神分裂症随后的临床表现；（2）在临床表现出现之前，婴儿期和青春期的一段静止期；（3）在成年早期出现精神病症状；（4）多巴胺（D2）受体在某些情况下受累而在其他情况下不累及，这可以解释为什么部分但不是所有患者对典型抗精神病药物治疗有反应；（5）一些患者持续存在神经退行性变化和认知衰退。我们提出，由于N-甲基-D-天冬氨酸受体功能低下可导致人类精神病以及大鼠大脑中的皮质边缘神经退行性变化，并且由于这些变化可被某些抗精神病药物（包括非典型抗精神病药物（氯氮平、奥氮平、氟哌拉平））预防，因此更好地理解N-甲基-D-天冬氨酸受体功能低下机制以及预防其在大鼠大脑中神经退行性后果的方法，可能会改善精神分裂症的药物治疗。
