Dopamine D(2)-D(3) receptor heteromers: pharmacological properties and therapeutic significance

Heteromerization of dopamine receptors has been shown for both the D1/D5 and D2/D3/D4 receptor families, which couple positively and negatively, respectively, to adenylyl cyclase. The present article reviews data on dopamine heteromers formed by D3, focusing in particular on associations with their D2 counterparts. Certain antiparkinsonian agents, like the preferential and high efficacy D3 > D2 agonists, pramipexole, and ropinirole, show amplified potency at D2–D3 heteromers versus constituent monomers. Accordingly, in cells cotransfected with D2 and D3 receptors, pramipexole, and ropinirole suppress forskolin (FK)- stimulated cAMP production with higher potencies as compared to cells transfected with D2 or D3 receptors only. Furthermore, in cells cotransfected with D2 and an excess of D3 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 D2 with an excess of D3 receptors. A hypothetical relationship of the above observations to the pathophysiology and possibly treatment of neuropsychiatric diseases is discussed.