Partial agonist actions at dopamine D 2L receptors are modified by co-transfection of D 3 receptors: Potential role of heterodimer formation

Abstract

The effects of aripiprazole, S33592, bifeprunox, N-desmethylclozapine and preclamol acting as partial agonists on recombinant D 2L and D 3 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 D 2L receptors coupled with adenylyl cyclase, but they behave as antagonists on co-expression of D 3 with D 2L receptors. These data raise the intriguing hypothesis that antipsychotic actions of “partial agonists” such as aripiprazole may not reflect inefficient stimulation of D 2 and/or D 3 receptors but, by analogy with other antipsychotics, may instead represent a blockade of D 2/D 3 heterodimers (and/or D 3 receptors) that are “weakly” coupled to transduction mechanisms postsynaptically of the dopaminergic pathway.