ACTIVATION OF HIPPOCAMPAL ADENOSINE A(3) RECEPTORS PRODUCES A DESENSITIZATION OF A(1) RECEPTOR-MEDIATED RESPONSES IN RAT HIPPOCAMPUS

The adenosine A(3) receptor is expressed in brain, but the consequence s of activation of this receptor on electrophysiological activity are unknown. We have characterized the actions of a selective adenosine A( 3) receptor agonist, -N-6-(3-iodobenzyl)-adenosine-5'-N-methyluronamid e (Cl-IB-MECA), and a selective A(3) receptor antagonist, henyl-1,,4-( +/-)-dihydropyridine-3,5-dicarboxylate (MRS 1191), in brain slices fro m rat hippocampus. In the CA1 region, activation of A(3) receptors had no direct effects on synaptically evoked excitatory responses, long-t erm potentiation, or synaptic facilitation. However, activation of A(3 ) receptors with Cl-IB-MECA antagonized the adenosine A(1) receptor-me diated inhibition of excitatory neurotransmission. The effects of Cl-I B-MECA were blocked by pretreatment with MRS 1191, which by itself had no effect on A(1) receptor-mediated responses. The presynaptic inhibi tory effects of baclofen and carbachol, mediated via GABA(B) and musca rinic receptors, respectively, were unaffected by Cl-IB-MECA. The maxi mal response to adenosine was unchanged, suggesting that the primary e ffect of Cl-IB-MECA was to reduce the affinity of adenosine for the re ceptor rather than to uncouple it. Similar effects could be demonstrat ed after brief superfusion with high concentrations of adenosine itsel f. Under normal conditions, endogenous adenosine in brain is unlikely to affect the sensitivity of A(1) receptors via this mechanism. Howeve r, when brain concentrations of adenosine are elevated (e.g., during h ypoxia, ischemia, or seizures), activation of A(3) receptors and subse quent heterologous desensitization of A(1) receptors could occur, whic h might limit the cerebroprotective effects of adenosine under these c onditions.