Age-dependent decrease in adenosine A(1) receptor binding sites in the ratbrain - Effect of cis unsaturated free fatty acids

Unsaturated free fatty acids and adenosine operate two neuromodulatory syst ems with opposite effects on neuronal function. Here, we tested if fatty ac ids controlled inhibitory adenosine A(1) receptors. Arachidonate (AA, 10 mu m) decreased the B-max of an A(1) receptor agonist, (R)-[H-3]phenylisopropy ladenosine (PIA; from 812 to 267 fmol.mg(-1) protein), and antagonist, [H-3 ]1,3-dipropyl-8-cyclopentylxanthine (DPCPX; from 994 to 311 fmol.mg(-1) pro tein) and decreased the K-d of [H-3]PIA (from 1.20 to 0.57 nm) binding to b rain membranes of young adult rats (2 months old), these effects being mimi cked by other cis but not trans unsaturated or saturated fatty acids. AA (1 0 mum) increased the potency of the A(1) receptor agonist, 2-chloroadenosin e to inhibit hippocampal synaptic transmission in young adult rats (EC50 de creased from 337 to 237 nm), which may constitute a safety feedback mechani sm to control AA-induced neurotoxicity. Upon aging, there were increased fr ee fatty acid levels and a concomitant decreased density of A(1) receptors. This was more marked in hippocampal nerve terminals of aged rats (24 month s old) and may be the determinant factor contributing to the lower potency of 2-choloroadenosine in aged rats (EC50 = 955 nm), in spite of the decreas ed K-d of PIA binding upon aging. The effects of AA on A(1) receptor bindin g were attenuated upon aging, AA being devoid of effects in aged rats. Acco rdingly, AA (10 mum) failed to modify the potency of 2-choloroadenosine in aged rats (EC50 = 997 nm). However, albumin, which quenches free fatty acid s, increased A(1) receptor density by 65% and 2-chloroadenosine potency (EC 50 = 703 nm) in aged rats, suggesting that the increased fatty acids levels in aged rats may contribute to the decreased potency of A(1) receptor agon ists in aged rats. Also, the observed saturation of the control by AA of A( 1) receptors may contribute to the decreased adaptability of neuromodulatio n to different firing conditions in aged rats.