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Anatomy of adenosine A_2A receptors in brain

Morphological substrates for integration of striatal function

From the Departments of Pharmacology (Dr. Rosin), Cardiovascular Medicine (Drs. Hettinger, Lee, and Linden), and Molecular Physiology and Biological Physics (Dr. Linden), University of Virginia Health Sciences Center, Charlottesville, VA.

Address correspondence and reprint requests to Dr. Diane L. Rosin, Department of Pharmacology, University of Virginia Health System, P.O. Box 800735, 1300 Jefferson Park Avenue, Charlottesville, VA 22908-0735; e-mail: dr5e{at}Virginia.edu

A_2A adenosine receptors (A_2ARs) are expressed with the greatest abundance in the striatum and other nuclei of the basal ganglia. The segregated expression of A_2ARs on the GABAergic striatopallidal medium spiny neurons, where A_2AR and D₂ dopamine receptor mRNAs are colocalized, and the opposing functional interaction between adenosine and dopamine suggest that A_2ARs may be an important therapeutic target. To further explore the role of A_2ARs in the synaptic organization of the basal ganglia, the authors developed an antibody directed against the purified A_2AR. Immunohistochemical studies in rat brain showed dense labeling of the neuropil in the striatum, nucleus accumbens, and olfactory tubercles with lighter labeling of terminals in the globus pallidus (GP), where A_2AR transcript is not detected. Stimulation of A_2ARs on GP terminals may facilitate GABAergic signaling and contribute to the overactivation observed in Parkinson’s disease (PD). Analysis at the ultrastructural level allowed a more detailed characterization of the mechanism(s) of A_2A-mediated control of striatal output. In the striatum, terminals expressing A_2ARs accounted for 25% of the labeled elements. These presynaptic receptors may facilitate excitatory glutamatergic, inhibitory GABAergic, and possibly cholinergic striatal transmission. However, the majority of striatal A_2AR immunoreactivity was found on postsynaptic elements, including dendrites of striatopallidal neurons, in which A_2AR and GABA immunoreactivity is colocalized. Activation of these receptors may promote GABAergic signaling in striatopallidal output neurons and their local axon collaterals in the striatum. Many of the A_2A-labeled dendrites were contacted by terminals forming asymmetric (excitatory) possibly glutamatergic synapses. Using the vesicular glutamate transporters (VGLUTs) as markers of glutamatergic terminals, the authors have found that VGLUT1-immunoreactive (ir) terminals make asymmetric contacts on A_2A-ir spines and spine heads in the striatum, suggesting that regulation of striatal output by A_2AR stimulation may involve facilitation of the cortical glutamatergic excitatory input to striatopallidal neurons. These ultrastructural findings suggest several pathways through which A_2A receptor blockade may act to dampen the elevated striatopallidal GABAergic signaling that occurs in PD.

The current affiliation for Dr. Lee is Department of Pharmacology, Emory University School of Medicine, Atlanta, GA.

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