ドパミン受容体の多様性と抗精神病薬の及ぼす影響

抄録

There have been many efforts to develop novel antipsychotic drugs with improved clinical efficacy and reduced side effects such as extrapyramidal side effects and hyperprolactinemia. Recent evidences from studies on the effects of novel antipsychotic drugs such as clozapine on neurotransmitter receptors are prompting reconsideration of the dopaminergic hypothesis of schizophrenia. This paper gives an overview of the current understanding, including our data, of the effects of several antipsychotics on dopamine receptor subtypes. The recent cloning of dopamine receptors has revealed that multiple dopamine receptor subtypes are generated from at least five distinct dopamine receptor genes. Aripiprazole, a candidate for a novel antipsychotic, has an antagonistic activity against dopamine D₂ receptors with a high affinity, but has a weaker potency to up-regulate D₂ receptors than haloperidol in the striatum and inhibitory effects on D₂-receptor binding activities and mRNA in the pituitary, when it is chronically administrated to rats. Thus the occupancy or influences in D₂ receptors in the striatum are involved in the extrapyramidal side effects of typical antipsychotic drugs. These studies provide new leads to understand the pathophysiology and causes of schizophrenia and to develop more effective and safe methods of treatment.