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.