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 A1 receptors. Arachidonate (AA, 10 microM) decreased the Bmax of an A1 receptor agonist, (R)-[3H]phenylisopropyladenosine (PIA; from 812 to 267 fmol x mg(-1) protein), and antagonist, [3H]1,3-dipropyl-8-cyclopentylxanthine (DPCPX; from 994 to 311 fmol x mg(-1) protein) and decreased the Kd of [3H]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 microM) increased the potency of the A1 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 A1 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 Kd of PIA binding upon aging. The effects of AA on A1 receptor binding were attenuated upon aging, AA being devoid of effects in aged rats. Accordingly, AA (10 microM) failed to modify the potency of 2-choloroadenosine in aged rats (EC50 = 997 nM). However, albumin, which quenches free fatty acids, increased A1 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 A1 receptor agonists in aged rats. Also, the observed saturation of the control by AA of A1 receptors may contribute to the decreased adaptability of neuromodulation to different firing conditions in aged rats.
Cunha
R A
RA
Laboratory of Neurosciences, Faculty of Medicine, University of Lisbon, Lisbon, Portugal. racunha@clix.pt
Constantino
M D
MD
Fonseca
E
E
Ribeiro
J A
JA
D015762:2-Chloroadenosine / Q000737:chemistry; D000367:Age Factors; D000375:Aging; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D001665:Binding Sites; D001921:Brain / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006624:Hippocampus / Q000378:metabolism; D007700:Kinetics; D008297:Male; D010660:Phenylisopropyladenosine / Q000737:chemistry; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D018047:Receptors, Purinergic P1 / Q000737:chemistry*; D013997:Time Factors; D014970:Xanthines / Q000494:pharmacology
D018047:Receptors, Purinergic P1; D014970:Xanthines; D015762:2-Chloroadenosine; D016718:Arachidonic Acid; D010660:Phenylisopropyladenosine; C051360:1,3-dipropyl-8-cyclopentylxanthine