Presynaptic adenosine receptor heteromers as key modulators of glutamatergic and dopaminergic neurotransmission in the striatum

Adenosine plays a very significant role in modulating striatal glutamatergic and dopaminergic neurotransmission. In the present essay we first review the extensive evidence that indicates this modulation is mediated by adenosine A₁ and A_2A receptors (A₁Rs and A_2ARs) differentially expressed by the components of the striatal microcircuit that include cortico-striatal glutamatergic and mesencephalic dopaminergic terminals, and the cholinergic interneuron. This microcircuit mediates the ability of striatal glutamate release to locally promote dopamine release through the intermediate activation of cholinergic interneurons. A₁Rs and A_2ARs are colocalized in the cortico-striatal glutamatergic terminals, where they form A₁R-A_2AR and A_2AR-cannabinoid CB₁ receptor (CB₁R) heteromers. We then evaluate recent findings on the unique properties of A₁R-A_2AR and A_2AR-CB₁R heteromers, which depend on their different quaternary tetrameric structure. These properties involve different allosteric mechanisms in the two receptor heteromers that provide fine-tune modulation of adenosine and endocannabinoid-mediated striatal glutamate release. Finally, we evaluate the evidence supporting the use of different heteromers containing striatal adenosine receptors as targets for drug development for neuropsychiatric disorders, such as Parkinson's disease and restless legs syndrome, based on the ability or inability of the A_2AR to demonstrate constitutive activity in the different heteromers, and the ability of some A_2AR ligands to act preferentially as neutral antagonists or inverse agonists, or to have preferential affinity for a specific A_2AR heteromer.