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 them^4,5, 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.