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The widespread biological actions of the neurotransmitter dopamine (DA) are mediated by two classes of receptor, the D1 class (D1 and D5) and the D2 class (D2, D3, and D4), 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 D1 and D2 class receptors. To address this issue from a functional point of view, we elicited striatal Fos by combined administration of a D1 class and a D2 class agonist either in the presence or absence of the fast sodium channel blocker tetrodotoxin (TTX). Striatal Fos elicited by direct D1/D2 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 D2 class of receptors, amphetamine-stimulated Fos and motor behavior were attenuated dose-dependently by the selective D2 antagonist L-741,626, but not by the selective D3 antagonist U99194A or the D4-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 D1 and D2 receptors, the present findings taken together suggest the intriguing possibility that D1/D2 synergism may be mediated by D1 and D2 receptors residing on separate striatal neurons and interacting in a manner that is not dependent on action potentials.

the journal of neuroscience/the journal of neuroscience

Dopamine D1 Receptors Synergize with D2, But Not D3 or D4, Receptors in the Striatum without the Involvement of Action Potentials