Adenosine-dopamine interactions in the pathophysiology and treatment of CNS disorders

Adenosine-dopamine interactions in the central nervous system (CNS) have been studied for many years in view of their relevance for disorders of the CNS and their treatments. The discovery of adenosine and dopamine receptor containing receptor mosaics (RM, higher-order receptor heteromers) in the striatum opened up a new understanding of these interactions. Initial findings indicated the existence of A(2A)R-D(2)R heterodimers and A(1)R-D(1)R heterodimers in the striatum that were followed by indications for the existence of striatal A(2A)R-D(3)R and A(2A)R-D(4)R heterodimers. Of particular interest was the demonstration that antagonistic allosteric A(2A)-D(2) and A(1)-D(1) receptor-receptor interactions take place in striatal A(2A)R-D(2)R and A(1)R-D(1)R heteromers. As a consequence, additional characterization of these heterodimers led to new aspects on the pathophysiology of Parkinson's disease (PD), schizophrenia, drug addiction, and l-DOPA-induced dyskinesias relevant for their treatments. In fact, A(2A)R antagonists were introduced in the symptomatic treatment of PD in view of the discovery of the antagonistic A(2A)R-D(2)R interaction in the dorsal striatum that leads to reduced D(2)R recognition and G(i/o) coupling in striato-pallidal GABAergic neurons. In recent years, indications have been obtained that A(2A)R-D(2)R and A(1)R-D(1)R heteromers do not exist as heterodimers, rather as RM. In fact, A(2A)-CB(1)-D(2) RM and A(2A)-D(2)-mGlu(5) RM have been discovered using a sequential BRET-FRET technique and by using the BRET technique in combination with bimolecular fluorescence complementation. Thus, other pathogenic mechanisms beside the well-known alterations in the release and/or decoding of dopamine in the basal ganglia and limbic system are involved in PD, schizophrenia and drug addiction. In fact, alterations in the stoichiometry and/or topology of A(2A)-CB(1)-D(2) and A(2A)-D(2)-mGlu5 RM may play a role. Thus, the integrative receptor-receptor interactions in these RM give novel aspects on the pathophysiology and treatment strategies, based on combined treatments, for PD, schizophrenia, and drug addiction.