中枢神経系のdopamine受容体に関する研究 第2編 抗パーキンソン病薬ならびに抗精神病薬反復投与によるdopamine受容体の調節

Long-term drug studies in animals using antiparkinsonian drugs (L-dopa and bromocriptine) and neuroleptics (chlorpromazine and haloperidol) can provide valuable clinical information on the mechanism of drug action and can contribute to a better understanding of the side effects of such therapy. Moreover, it has been suggested that the molecular action of these drugs involves dopamine receptors in the brain. Recently, it was proposed that the dopamine receptor exists in two forms: a D(1)-dopamine receptor, which is coupled to dopamine sensitive adenilate cyclase, and a D(2)-dopamine receptor, which is uncoupled. I have established D(1)-dopamine-radioreceptor assay and D(2)-dopamine-radioreceptor assay using [(3)H]-dopamine as a ligand, then I studied the effects of chronic administration of these drugs on two forms of dopamine receptors. It is well known that most patients on prolonged L-dopa therapy either become refractory to the drug, or develop "on-off" phenomena or dyskinesias. In this study, an increase in high affinity binding sites of D(1)-dopamine receptor was detected, whereas D(2)-dopamine receptor subsensitivity was observed following long-term L-dopa therapy. On the other hand, after bromocriptine treatment for 14days, the high affinity binding sites of D(1)-and D(2)-dopamine receptors were increased in the rat striatum. The finding that long-term bromocriptine therapy increases D(1)-and D(2)-dopamine receptors may explain, in part, the efficacy of combination bromocriptine and L-dopa treatment. After chlorpromazine treatment for 14 days, the high affinity binding sites of D(1)-and D(2)-dopamine receptors were slightly increased in rat striatum, and after haloperidol treatment for 14 days, the high affinity binding sites of D(2)-dopamine receptor were also slightly increased in rat striatum. Therefore, it was suggested that symptoms of extrapyramidal side effects after long-term neuroleptic treatment reflect a functional supersensitivity of dopamine receptors in the rat striatum.