Dopamine activation of the arachidonic acid cascade as a basis for D1D2 receptor synergism

Abstract

UNDERSTANDING the actions of the neurotransmitter dopamine in the brain is important in view of its roles in neuropsychiatric illnesses1. Dopamine D1 receptors, which stimulate both adenylyl cyclase2 and phospholipase C3, and D2 receptors, which inhibit them4,5, can nevertheless act synergistically to produce many electrophysiological and behavioural responses6. Because this functional synergism can occur at the level of single neurons, another, as yet unidentified, signalling pathway activated by dopamine has been hypothesized7. We report here that in Chinese hamster ovary (CHO) cells transfected with the D2 receptor complementary DNA, D2 agonists potently enhance arachidonic acid release, provided that such release has been initiated by stimulating constitutive purinergic receptors or by increasing intracellular Ca2+. In CHO cells expressing D1 receptors, D1 agonists exert no such effect. When D1 and D2 receptors are coexpressed, however, activation of both subtypes results in a marked synergistic potentiation of arachidonic acid release. The numerous actions of arachidonic acid and its metabolites in neuronal signal transduction8 suggest that facilitation of its release may be implicated in dopaminergic responses, such as feedback inhibition mediated by D2 autoreceptors, and may constitute a molecular basis for D1/D2 receptor synergism.