It is well known that the dopamine D(3) receptor plays a critical role in several psychological disorders, such as drug dependence. The present study was designed to investigate the influence of lacking dopamine D(3) receptors in dopamine-induced G-protein activation and Ca(2+) influx in the mouse forebrain. The deletion of dopamine D(3) receptor gene caused the enhancement of dopamine-induced G-protein activation in the limbic forebrain of dopamine D(3) receptor knockout (D(3)KO) mice. Furthermore, the dopamine-induced Ca(2+) influx was enhanced in the coculture of neuron/glia cells obtained from the forebrain of D(3)KO mice. The present data provide direct evidence that a deletion of central dopamine D(3) receptor enhances the dopamine D(1)/D(2) receptor-mediated intracellular signaling.