The depolarization block hypothesis of neuroleptic action: implications for the etiology and treatment of schizophrenia.
The depolarization block hypothesis of neuroleptic action: implications for the etiology and treatment of schizophrenia.
复制标题
抗精神病药作用的去极化阻滞假说：对精神分裂症的病因学和治疗的影响。
DOI：
10.1007/978-3-7091-9211-5_6
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发表时间：
1992
期刊：
影响因子：
--
通讯作者：
Grace,AA
中科院分区：
文献类型：
--
作者：
Grace,AA
已知抗精神病药物在服用后不久就会阻断多巴胺受体，导致多巴胺神经元放电和多巴胺周转增加。尽管如此，在产生治疗效果之前，抗精神病药物必须反复给精神分裂症患者服用。大鼠多巴胺神经元的记录显示，慢性抗精神病药物治疗通过过度兴奋或去极化阻断导致多巴胺神经元放电的时间依赖性失活。此外，抗精神病药物反应的临床特征似乎与受影响的多巴胺系统相对应：抗精神病药物在精神分裂症患者中发挥治疗作用，使边缘相关的腹侧被盖区多巴胺神经元失活，而沉淀锥体外系副作用的药物导致运动相关的黑质多巴胺细胞去极化阻滞。关于抗精神病药物的作用，一个尚未解决的因素是多巴胺转换和去极化阻断之间的关系——也就是说，为什么在抗精神病药物治疗后，如果多巴胺细胞不再放电，多巴胺释放或转换的显著水平仍然存在？我们使用抗精神病药诱导的去极化阻滞急性模型来解决这个问题。在该模型中，大鼠局部多巴胺损伤1个月后记录的多巴胺细胞可以通过急性给予中等剂量氟哌啶醇而进入去极化阻滞。然而，相同剂量的氟哌啶醇可以有效地增加完整大鼠纹状体中的多巴胺水平，却不能改变受损大鼠的多巴胺水平。这与一种模型是一致的，在这种模型中，抗精神病药物通过引起DA细胞的去极化阻断来发挥其治疗作用，从而阻止多巴胺神经元对外部刺激的进一步激活。因此，减弱多巴胺系统对刺激的反应性可能与抗精神病药物的治疗作用更相关，而不是受体阻断或多巴胺绝对水平的降低，这可能是在这个高度可塑性的系统中通过稳态适应来规避的。
Antipsychotic drugs are known to block dopamine receptors soon after their administration, resulting in an increase in dopamine neuron firing and dopamine turnover. Nonetheless, antipsychotic drugs must be administered repeatedly to schizophrenics before therapeutic benefits are produced. Recordings from dopamine neurons in rats have revealed that chronic antipsychotic drug treatment results in the time-dependent inactivation of dopamine neuron firing via over-excitation, or depolarization block. Furthermore, the clinical profile of the response to antipsychotic drugs appears to correspond to the dopamine system affected: antipsychotic drugs that exert therapeutic actions in schizophrenics inactivate dopamine neuron firing in the limbic-related ventral tegmental area, whereas drugs that precipitate extrapyramidal side effects cause depolarization block of the motor-related substantia nigra dopamine cells.One factor that remains unresolved with regard to the actions of antipsychotic drugs is the relationship between dopamine turnover and depolarization block — i.e., why does a significant level of dopamine release or turnover remain after antipsychotic drug treatment if dopamine cells are no longer firing? We addressed this question using an acute model of neuroleptic-induced depolarization block. In this model, dopamine cells recorded in rats one month after partial dopamine lesions could be driven into depolarization block by the acute administration of moderate doses of haloperidol. However, similar doses of haloperidol, which were effective at increasing dopamine levels in the striatum of intact rats, failed to change dopamine levels in lesioned rats. This is consistent with a model in which neuroleptic drugs exert their therapeutic effects in schizophrenics by causing depolarization block in DA cells, thereby preventing further activation of dopamine neuron firing in response to external stimuli. Thus, attenuating the responsivity of the dopamine system to stimuli may be more relevant to the therapeutic actions of antipsychotic drugs than receptor blockade or decreases in absolute levels of dopamine, which could presumably be circumvented by homeostatic adaptations in this highly plastic system.