Dopamine D2-D3 receptor heteromers: pharmacological properties and therapeutic significance

Heteromerization of dopamine receptors has been shown for both the D(1)/D(5) and D(2)/D(3)/D(4) receptor families, which couple positively and negatively, respectively, to adenylyl cyclase. The present article reviews data on dopamine heteromers formed by D(3), focusing in particular on associations with their D(2) counterparts. Certain antiparkinsonian agents, like the preferential and high efficacy D(3)>D(2) agonists, pramipexole, and ropinirole, show amplified potency at D(2)-D(3) heteromers versus constituent monomers. Accordingly, in cells cotransfected with D(2) and D(3) receptors, pramipexole, and ropinirole suppress forskolin (FK)-stimulated cAMP production with higher potencies as compared to cells transfected with D(2) or D(3) receptors only. Furthermore, in cells cotransfected with D(2) and an excess of D(3) receptors, the partial agonists aripiprazole, S33592, bifeprunox, N-desmethylclozapine, and preclamol lose agonist properties and abolish the actions of quinpirole. Then, partial agonists are transformed into antagonists upon cotransfection of D(2) with an excess of D(3) receptors. A hypothetical relationship of the above observations to the pathophysiology and possibly treatment of neuropsychiatric diseases is discussed.