Dopamine D1 receptors synergize with D2, but not D3 or D4, receptors in the striatum without the involvement of action potentials.

The widespread biological actions of the neurotransmitter dopamine (DA) are mediated by two classes of receptor, the D(1) class (D(1) and D(5)) and the D(2) class (D(2), D(3), and D(4)), which interact synergistically in many paradigms, such as DA agonist-stimulated motor behavior and striatal c-fos expression. Understanding the mechanism(s) of this interaction has been impeded by a controversy regarding the cellular localization of D(1) and D(2) class receptors. To address this issue from a functional point of view, we elicited striatal Fos by combined administration of a D(1) class and a D(2) class agonist either in the presence or absence of the fast sodium channel blocker tetrodotoxin (TTX). Striatal Fos elicited by direct D(1)/D(2) stimulation was not reduced by TTX. By contrast, TTX greatly attenuated the Fos response evoked by cocaine or GBR 12909. In separate experiments using antagonists that distinguish among members of the D(2) class of receptors, amphetamine-stimulated Fos and motor behavior were attenuated dose-dependently by the selective D(2) antagonist L-741,626, but not by the selective D(3) antagonist U99194A or the D(4)-selective antagonist L-745,870. Because Fos expression in the paradigms that were used occurs in enkephalin-negative striatonigral neurons, which show limited coexpression of D(1) and D(2) receptors, the present findings taken together suggest the intriguing possibility that D(1)/D(2) synergism may be mediated by D(1) and D(2) receptors residing on separate striatal neurons and interacting in a manner that is not dependent on action potentials.