Central versus peripheral mediation of responses to adenosine receptor agonists: evidence against a central mode of action

Although adenosine and its analogs have potent effects on the peripheral and central nervous systems, the actions of systemically administered adenosine analogs on the central nervous system are poorly understood. We have previously shown that adenosine analogs depress hippocampal-evoked responses (fEPSPs) in a brain slice preparation, and in the present study, we observed that local pressure ejection of adenosine or R-phenylisopropyladenosine (R-PIA) also reduced the fEPSP recorded in situ in a theophylline-reversible manner. However, systemic administration of R-PIA in up to 1000 times the behaviorally active dose failed to attenuate the fEPSP amplitude. Similar observations were made with systemic injections of 2-chloroadenosine and N-ethylcarboxamidoadenosine, both of which are active in behavioral studies following intraperitoneal or intracerebroventricular injection. Autoradiography showed systemically injected [3H]PIA did not enter the brain in significant concentrations, and this observation was confirmed using microdialysis brain perfusion. These results suggest that systemically administered adenosine analogs do not affect synaptic neurotransmission in the hippocampus because they fail to reach the appropriate receptors.