Adenosine A 2A receptors and basal ganglia physiology

Abstract

Adenosine A 2A receptors are highly enriched in the basal ganglia system. They are predominantly expressed in enkephalin-expressing GABAergic striatopallidal neurons and therefore are highly relevant to the function of the indirect efferent pathway of the basal ganglia system. In these GABAergic enkephalinergic neurons, the A 2A receptor tightly interacts structurally and functionally with the dopamine D 2 receptor. Both by forming receptor heteromers and by targeting common intracellular signaling cascades, A 2A and D 2 receptors exhibit reciprocal antagonistic interactions that are central to the function of the indirect pathway and hence to basal ganglia control of movement, motor learning, motivation and reward. Consequently, this A 2A/D 2 receptors antagonistic interaction is also central to basal ganglia dysfunction in Parkinson's disease. However, recent evidence demonstrates that, in addition to this post-synaptic site of action, striatal A 2A receptors are also expressed and have physiological relevance on pre-synaptic glutamatergic terminals of the cortico-limbic-striatal and thalamo-striatal pathways, where they form heteromeric receptor complexes with adenosine A 1 receptors. Therefore, A 2A receptors play an important fine-tuning role, boosting the efficiency of glutamatergic information flow in the indirect pathway by exerting control, either pre- and/or post-synaptically, over other key modulators of glutamatergic synapses, including D 2 receptors, group I metabotropic mGlu 5 glutamate receptors and cannabinoid CB 1 receptors, and by triggering the cAMP-protein kinase A signaling cascade.