Dopamine-induced functional activation of Gα mediated by dopamine D-like receptor in rat cerebral cortical membranes.

Although multiple roles of dopamine through D-like (D and D) and D-like (D, D, and D) receptors are initiated primarily through stimulation or inhibition of adenylyl cyclase via G or G, respectively, there have been many reports indicating diverse signaling mechanisms that involve alternative G protein coupling. In this study, dopamine-induced Gα activation in rat brain membranes was investigated. Agonist-induced Gα activation was assessed by increase in guanosine-5'--(3-[S]thio)triphosphate ([S]GTPγS) binding to Gα determined by [S]GTPγS binding/immunoprecipitation assay in rat brain membranes. Dopamine-stimulated Gα functionality was highest in cortex as compared to hippocampus or striatum. In cerebral cortical membranes, this effect was mimicked by benzazepine derivatives with agonist properties at dopamine D-like receptors, that is, SKF83959, SKF83822, (+)-SKF81297, (+)-SKF38393, and SKF82958, but not by the compounds with dopamine D-like receptor agonist properties except for aripiprazole. Against expectation, stimulatory effects were also induced by SKF83566, (+)-SCH23390, and pergolide. The pharmacological profiling by using a series of antagonists indicated that dopamine-induced response was mediated through dopamine D-like receptor, which was distinct from the receptor involved in 5-HT-induced response (5-HT receptor). Conversely, the responses induced by SKF83566, (+)-SCH23390, and pergolide were most likely mediated by 5-HT receptor, but not by dopamine D-like receptor. Caution should be paid when interpreting the experimental data, especially in behavioral pharmacological research, in which SKF83566 or (+)-SCH23390 is used as a standard selective dopamine D-like receptor antagonist. Also, possible clinical implications of the agonistic effects of pergolide on 5-HT receptor has been mentioned.