Age-dependent decrease in adenosine A1 receptor binding sites in the rat brain -: Effect of cis unsaturated free fatty acids

Unsaturated free fatty acids and adenosine operate two neuromodulatory systems with opposite effects on neuronal function. Here, we tested if fatty acids controlled inhibitory adenosine A(1) receptors. Arachidonate (AA, 10 mum) decreased the B-max of an A(1) receptor agonist, (R)-[H-3]phenylisopropyladenosine (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) protein) and decreased the K-d of [H-3]PIA (from 1.20 to 0.57 nm) binding to brain membranes of young adult rats (2 months old), these effects being mimicked by other cis but not trans unsaturated or saturated fatty acids. AA (10 mum) increased the potency of the A(1) receptor agonist, 2-chloroadenosine to inhibit hippocampal synaptic transmission in young adult rats (EC50 decreased from 337 to 237 nm), which may constitute a safety feedback mechanism to control AA-induced neurotoxicity. Upon aging, there were increased free fatty acid levels and a concomitant decreased density of A(1) receptors. This was more marked in hippocampal nerve terminals of aged rats (24 months 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 decreased K-d of PIA binding upon aging. The effects of AA on A(1) receptor binding were attenuated upon aging, AA being devoid of effects in aged rats. Accordingly, AA (10 mum) failed to modify the potency of 2-choloroadenosine in aged rats (EC50 = 997 nm). However, albumin, which quenches free fatty acids, increased A(1) receptor density by 65% and 2-chloroadenosine potency (EC50 = 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 agonists in aged rats. Also, the observed saturation of the control by AA of A(1) receptors may contribute to the decreased adaptability of neuromodulation to different firing conditions in aged rats.