Glutamate mGlu5-Adenosine A2A-Dopamine D2 Receptor Interactions in the Striatum. Implications for Drug Therapy in Neuro-psychiatric Disorders and Drug Abuse

There is growing evidence for the existence of not only homomeric, but also functional heteromeric receptor complexes, particularly involving G protein coupled receptors (GPCRs). These include adenosine A2A-dopamine D2 and adenosine A2A-glutamate mGlu5 receptor complexes. The role of these receptor complexes in receptor function seems to be multiple, involving hetero-modulation of ligand recognition, signalling and trafficking. The preferential localization of A2A-D2 and A2A-mGlu5 receptor complexes is in the dendritic spines of striatopallidal GABAergic neurons. Results obtained from behavioral and in vivo microdialysis experiments have shown an important role of mGlu5-A2A-D2 receptor interactions in the modulation of the function of the striatopallidal GABAergic neurons. The striatopallidal GABAergic neurons play a key role in the pathophysiology of basal ganglia disorders, like Parkinson's disease, and it is a common pathway for the rewarding effects of opiates and psychostimulants and for the antipsychotic effects of neuroleptics. The formation of receptor complexes modifies the single receptor transducing characteristics and leads to the appearance of “emergent properties”. Thus, the study of mGlu5-A2A-D2 receptor interactions in the striatum reveals new properties of these GPCRs and gives indications for a new rational approach for drug therapy in neuro-psychiatric disorders and drug addiction.