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 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.
Maggio
Roberto
R
Department of Experimental Medicine, University of L'Aquila, Via Vetoi, Coppito 2, L'Aquila, Italy. roberto.maggio@univaq.it
Novi
Francesca
F
Rossi
Mario
M
Corsini
Giovanni U
GU
Millan
Mark J
MJ
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D005576:Colforsin / Q000494:pharmacology; D018491:Dopamine Agonists / Q000737:chemistry / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004347:Drug Interactions; D008954:Models, Biological; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000235:genetics; D050637:Receptors, Dopamine D3 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection / Q000379:methods
D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C113776:dopamine D2L receptor; D005576:Colforsin; D000262:Adenylyl Cyclases