Partial agonist actions of aripiprazole and the candidate antipsychotics S33592, bifeprunox, N-desmethylclozapine and preclamol at dopamine D2L receptors are modified by co-transfection of D3 receptors:: potential role of heterodimer fort-nation

Aripiprazole and the candidate antipsychotics, S33592, bife-prunox, N-desmethylclozapine (NDMC) and preclamol, are partial agonists at D-2 receptors. Herein, we examined their actions at D-2L and D-3 receptors expressed separately or together in COS-7 cells. In D-2L receptor-expressing cells co-transfected with (D-3 recepto r- insensitive) chimeric adenylate cyclase-V/VI, drugs reduced forskolin-stimulated cAMP production by similar to 20% versus quinpirole (48%). Further, quinpirole-induced inhibition was blunted by aripiprazole and S33592, confirming partial agonist properties. In cells co-transfected with equal amounts of D-2L and D-3 receptors (1 : 1), efficacies of aripiprazole and S33592 were attenuated. Further, in cells co-transfected with D-2L and an excess of D-3 receptors (1 : 3), aripiprazole and S33592 were completely inactive, and they abolished the actions of quinpirole. Likewise, bifeprunox, NDMC and preclamol lost agonist properties in cells co-transfected with D-2L and D-3 receptors. Accordingly, at split D-2trunk/D-3tail and D-3trunk/D-2tail chimeras, agonist actions of quinpirole were blocked by aripiprazole and S33592 that, like bifeprunox, NDMC and preclamol, were inactive alone. Conversely, when a 12 amino acid sequence in the third intracellular loop of D-3 receptors was replaced by the homologous sequence of D-2L receptors, aripiprazole, S33592, bifeprunox, NDMC and preclamol inhibited cAMP formation by similar to 20% versus quinpirole (42%). Moreover, at D2L receptor-expressing cells co-transfected with modified D-3i3(D2) receptors, drugs behaved as partial agonists. To summarize, low efficacy agonist actions of aripiprazole, S33592, bifeprunox, NDMC and preclamol at D-2L receptors are abrogated upon co-expression of D-3 receptors, probably due to physical association and weakened coupling efficacy. These findings have implications for the functional profiles of antipsychotics.