CHRONIC CONTINUOUS ADMINISTRATION OF NEUROLEPTIC DRUGS ALTERS CEREBRAL DOPAMINE-RECEPTORS AND INCREASES SPONTANEOUS DOPAMINERGIC ACTION IN THE STRIATUM
CHRONIC CONTINUOUS ADMINISTRATION OF NEUROLEPTIC DRUGS ALTERS CEREBRAL DOPAMINE-RECEPTORS AND INCREASES SPONTANEOUS DOPAMINERGIC ACTION IN THE STRIATUM
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DOI：
10.1038/296570a0
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发表时间：
1982-01-01
期刊：
影响因子：
64.8
通讯作者：
MARSDEN, CD
中科院分区：
文献类型：
--
作者：
MURUGAIAH, K;THEODOROU, A;MARSDEN, CD
精神分裂症的“多巴胺假说”指出，这种疾病是由于大脑中多巴胺机制的过度活跃。这一假说基于两个事实：（1）药物，如安非他明，可以增强大脑中多巴胺能神经传递，偶尔会引起精神分裂症性精神病;（2）急性服用用于治疗精神分裂症和其他精神病的神经安定药物，会导致大脑多巴胺受体阻滞，并引发一系列代偿性事件，试图克服这种作用。我们以前已经表明，给药的神经安定药物的大鼠长达18个月产生意想不到的effects 1，2：6个月后，所有的迹象表明，阻断多巴胺受体在纹状体消失，此后纹状体多巴胺受体的数量增加，并成为行为超敏感的多巴胺受体激动剂，如阿扑吗啡。我们现在表明，这种长期暴露于抗精神病药物完全改变纹状体多巴胺受体的其他特性，在完整的动物，这些变化与自发性过度活跃的纹状体多巴胺能机制。除非其他多巴胺能脑区，例如中脑边缘或中皮层区域，与纹状体的反应不同，否则抗精神病药的作用方式和精神分裂症的多巴胺假说可能必须重新考虑。
The ‘dopamine hypothesis’ of schizophrenia states that the illness is due to overactivity of dopamine mechanisms in the brain. This hypothesis is based on two facts: (1) drugs, such as amphetamine, that enhance dopaminergic neurotransmission in the brain, may occasionally provoke a schizophrenic psychosis; and (2) acute administration of neuroleptic drugs, which are used to treat schizophrenia and other psychotic illnesses, causes blockade of brain dopamine receptors and initiates a chain of compensatory events which attempt to overcome such an action. We have previously shown that administration of neuroleptic drugs to rats for up to 18 months produces unexpected effects1,2: after 6 months, all signs of blockade of dopamine receptors in the striatum have disappeared, and thereafter striatal dopamine receptors increase in number and become behaviourally supersensitive to administered dopamine agonists such as apomorphine. We now show that such chronic exposure to neuroleptics completely alters other characteristics of striatal dopamine receptors, and that in the intact animal, these changes are associated with spontaneous overactivity of striatal dopaminergic mechanisms. Unless other dopaminergic brain areas, for example in the mesolimbic or mesocortical regions, react differently from the striatum, the mode of action of neuroleptics, and the dopamine hypothesis of schizophrenia, may have to be reconsidered.