Partial agonist actions at dopamine D2L receptors are modified by co-transfection of D3 receptors: Potential role of heterodimer formation

The effects of aripiprazole, S33592, bifeprunox, N-desmethylclozapine and preclamol acting as partial agonists on recombinant D2L and D3 receptors expressed both separately and concomitantly in COS-7 cells are evaluated here. Aripiprazole, S33592, bifeprunox, N-desmethylclozapine and preclamol behave as partial agonists on D2L receptors coupled with adenylyl cyclase, but they behave as antagonists on co-expression of D3 with D2L receptors. These data raise the intriguing hypothesis that antipsychotic actions of “partial agonists” such as aripiprazole may not reflect inefficient stimulation of D2 and/or D3 receptors but, by analogy with other antipsychotics, may instead represent a blockade of D2/D3 heterodimers (and/or D3 receptors) that are “weakly” coupled to transduction mechanisms postsynaptically of the dopaminergic pathway.