中枢神経系のdopamine受容体に関する研究

第1編 dopamine受容体の生化学的ならびに薬理学的検討

抄録

Until recently, it was widely accepted that neuroleptics act by blocking the dopamine receptor. Many investigators have done binding studies in vitro using [³H]-neuroleptics as ligands. However, recent studies on rat brains suggest that [³H]-neuroleptics label not only the dopamine receptor, but other receptors as well.
In this study, the cross reactivities of numerous centrally acting drugs in dopamine-radioreceptor assay were different from those in spiroperidol-radioreceptor assay. Manganese enhanced the specific binding of [³H]-dopamine dramatically by 300% even at low concentrations, although manganese did not influence the specific binding of [³H]-spiroperidol. To differentiate dopamine and spiroperidol receptors in the rat brain, I solubilized these receptor molecules by treatment with detergent and examined the molecular weight by gel filtration. As compared with the elution volumes of marker proteins, the approximate molecular weight of solubilized dopamine receptors were about 200, 000 dalton (Stokes'radius: 5.0 nm) in the absence of manganese, and about 400, 000 dalton (Stokes'radius: 6.1 nm) in the presence of manganese. Moreover, manganese was found in the same fraction as the solubilized dopamine receptor. However, the molecular weight of the solubilized spiroperidol receptor was about 120, 000 dalton (Stokes'radius: 4.3 nm) in both the presence and absence of manganese.
These data suggest that manganese couples specifically with manganese-free dopamine receptors, and that this manganese-dopamine receptor complex may have a strong capacity to bind dopamine. On the other hand, the receptor activities of spiroperidol were independent of manganese. These findings suggest that the site of action of spiroperidol is a receptor different from authentic dopamine receptor.