Modification of adenosine modulation of acetylcholine release in the hippocampus of aged rats

Adenosine is a neuromodulator acting through inhibitory A(1) receptors (A(1)Rs) and facilitatory A(2A)Rs. Since A(2A)R antagonists attenuate memory deficits in aged animals and memory deficits might involve a decreased cholinergic function, we investigated how aging affects the density and function of adenosine receptors in rat hippocampal cholinergic terminals. In young adult (2 months) rats, 64 and 36% of cholinergic terminals (immunopositive for vesicular ACh transporters) possessed A(1)Rs and A(2A)Rs, respectively. In aged (24 months) rats, the percentage of cholinergic terminals with A(1)Rs was preserved, whereas that with A(2A)Rs was larger (49%). In young adults adenosine only tonically inhibited ACh release through A(1)Rs, whereas in aged rats there was a greater A(1)R-mediated inhibition and a simultaneous A(2A)R-mediated facilitation of ACh release. Thus, the enhanced A(2A)R density and facilitation compensates for the greater tonic A(1)R modulation, preserving the global adenosine modulation of ACh release in aged rats. Furthermore, since A(2A)R antagonists inhibit ACh release, the beneficial effects of A(2A)R antagonists on memory in aged rats might not result from ACh release modulation.