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 A_2ARs. Since A_2AR 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 A_2ARs, respectively. In aged (24 months) rats, the percentage of cholinergic terminals with A₁Rs was preserved, whereas that with A_2ARs 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 A_2AR-mediated facilitation of ACh release. Thus, the enhanced A_2AR density and facilitation compensates for the greater tonic A₁R modulation, preserving the global adenosine modulation of ACh release in aged rats. Furthermore, since A_2AR antagonists inhibit ACh release, the beneficial effects of A_2AR antagonists on memory in aged rats might not result from ACh release modulation.