Dopamine D-1 receptors synergize with D-2, but not D-3 or D-4, 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 paradi gms, such as DA agonist-stimulated motor behavior and striatal c-fos expres sion. Understanding the mechanism(s) of this interaction has been impeded b y a controversy regarding the cellular localization of D-1 and D-2 class re ceptors. 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 ago nist either in the presence or absence of the fast sodium channel blocker t etrodotoxin (TTX). Striatal Fos elicited by direct D-1/D-2 stimulation was not reduced by TTX. By contrast, TTX greatly attenuated the Fos response ev oked by cocaine or GBR 12909. In separate experiments using antagonists tha t distinguish among members of the D-2 class of receptors, amphetamine-stim ulated Fos and motor behavior were attenuated dose-dependently by the selec tive D-2 antagonist L-741,626, but not by the selective D-3 antagonist U991 94A or the D-4-selective antagonist L-745,870. Because Fos expression in th e paradigms that were used occurs in enkephalin-negative striatonigral neur ons, 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 syn ergism may be mediated by D-1 and D-2 receptors residing on separate striat al neurons and interacting in a manner that is not dependent on action pote ntials.