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

Adenosine is a neuromodulator acting through inhibitory A1 receptors (A1Rs) and facilitatory A2ARs. Since A2AR 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 A1Rs and A2ARs, respectively. In aged (24 months) rats, the percentage of cholinergic terminals with A1Rs was preserved, whereas that with A2ARs was larger (49%). In young adults adenosine only tonically inhibited ACh release through A1Rs, whereas in aged rats there was a greater A1R-mediated inhibition and a simultaneous A2AR-mediated facilitation of ACh release. Thus, the enhanced A2AR density and facilitation compensates for the greater tonic A1R modulation, preserving the global adenosine modulation of ACh release in aged rats. Furthermore, since A2AR antagonists inhibit ACh release, the beneficial effects of A2AR antagonists on memory in aged rats might not result from ACh release modulation.