The ultrastructural localization of adenosine A2A receptors within the striatum will be evaluated using immunohistochemistry and electron microscopy techniques in an effort to determine the importance of adenosine as a neuromodulator in basal ganglia circuitry. Excitatory glutamatergic inputs from the cerebral cortex and thalamus as well as dopaminergic inputs from the midbrain innervate GABAergic medium spiny neurons projecting to the substantia nigra and globus pallidus. Striatal neurotransmission is also regulated by cholinergic and/or GABAergic interneurons. Adenosine, acting through A2A receptors, may serve to regulate striatal outputs at several levels. The proximity of A2A receptors to glutamatergic terminals in striatum will be studied in order to determine whether adenosine may act presynaptically to alter synaptic glutamate release and striatal output. Colocalization studies using A2A adenosine receptor antibodies in addition to markers for medium spiny projecting neurons (GABA and enkephalin or substance P containing) as well as cholinergic and GABAergic interneurons will provide a means to determine the site(s) of adenosine modulation. Parkinson's disease results from an imbalance in the regulation of striatal output neurons and both dopamine and glutamate abnormalities have been implicated in this disease. It has been proposed that antagonists of A2A receptors may be of therapeutic value as a means to reverse the dopamine deficiency characteristic of Parkinson's disease. This suggests that adenosine may act at A2A receptors to maintain critical signaling in the striatum. It is therefore important to determine how adenosine functions within the scope of striatal circuitry.
