Central Sites of Adenosine Action and Their Interaction with Various Drugs

Abstract

Adenosine receptors and adenosine uptake sites constitute interesting targets for the development of pharmacologic agents having sedative, anticonvulsant, antihypertensive and, possibly, anxiolytic properties. Specific probes now exist for both the receptor and the uptake site in brain. The available evidence indicates that either multiple populations or conformations of the receptor and uptake site are found in brain. Adenosine agonists bind to the receptor in a biphasic manner, suggesting the presence of two receptor subtypes, while antagonists apparently recognize a population of receptors that is only partially inhibited by various metal ions. We have recently tritium-labeled the adenosine uptake inhibitor dipyridamole (DPR) and show that it labels more adenosine uptake sites than [3H] nitrobenzylthioinosine (NBI), suggesting the existence of multiple subtypes of adenosine uptake sites. This is supported by the observation that NBI displaces [3H]DPR binding in a markedly biphasic manner. Autoradiographic analysis of [3H]DPR binding in guinea pig brain shows a heterogeneous distribution of sites, with areas such as the molecular layer of the cerebellum, superior colliculus, striatum, and cerebral cortex having high levels of both the receptor and uptake site. We suggest that those brain areas having high levels of both the adenosine receptor and uptake site may be sites of functionally relevant adenosinergic neuromodulation.