Ca<SUP>2+</SUP>チャネル活性元進モデル動物を用いたD<SUB>2</SUB>受容体関連薬物の評価法

Abstract

In order to investigate the novel treatment for neuro-psychiatric diseases which are caused by the neuronal dysfunctions, we newly developed an animal model which striatal dopaminergic (DA) neuronal system was markedly potentiated by a Ca2+ channel activator After administration of Bay K 8644 (BAY), a L-type Ca2+ channel activator, into rat caudate putamen, the increases of spontaneous locomotor activity (SLMA) and rearing appearences induced by a novel circumstance were significantly enhanced. These increases were due to the extraordinary efflux of DA in caudate putamen after administration of BAY. Pre-treatment of D1 and D2 antagonists markedly inhibited these increases of SLMA and rearing, although these treatments did not effect on the magnificent increase of DA efflux. Pre-treatment of D1 agonist, a dosage of larger 50 nmol of SKF 81297 (SKF), killed BAY treated rats. The smaller dosages of SKF, however, did not influence to the behavioral and biochemical changes seen after the treatment of BAY. Meanwhile, pre-treatments of bromocriptine and talipexole, significantly blocked BAY induced behavioral and biochemical changes, although single administration of each D2 agonist increased SLMA and rearing number, but not the DA efflux. These results suggest that the antagonistic mechanisms of D2 agonists on BAY-induced DA efflux and SLMA potentiation is due to their stimulating to autoreceptor. In conclusion, this animal model is useful for screening D2 agonists which have the anti-Parkinson, anti-schizophrenia and/or neuroprotective action.