Neuronal A1 receptors mediate increase in extracellular kynurenic acid after local intrastriatal adenosine infusion.
The naturally occurring purine nucleoside adenosine has pronounced anticonvulsant and neuroprotective properties and plays a neuromodulatory role in the CNS. Kynurenic acid (KYNA) is an astrocyte-derived, endogenous neuroinhibitory compound, which shares several of adenosine's properties. In a first attempt to examine possible interactions between these two biologically active molecules, adenosine was focally applied into the striatum of freely moving rats by reverse microdialysis, and changes in extracellular KYNA were monitored over time. A 2-h infusion of adenosine increased KYNA levels in a dose-dependent manner, with 10 mm of adenosine causing a twofold elevation within 1 h. This effect was reversible and was effectively blocked by coinfusion of the specific A1 adenosine receptor antagonist 8-cyclopentyltheophylline (100 microm). In contrast, coinfusion of adenosine with MSX-3 (100 microm), an A2A receptor antagonist, did not affect the adenosine-induced increase in KYNA levels. Local striatal perfusion with the A1 receptor agonist N6-cyclopentyladenosine (100 microm) mimicked the effect of adenosine, whereas perfusion with the A2A receptor agonist CGS-21680 (100 microm) was ineffective. Finally, we tested the effect of adenosine (10 mm) on extracellular KYNA in striata that had been injected with quinolinate (60 nmol/1 microL) 7 days earlier. In this neuron-depleted tissue, perfusion with adenosine failed to affect extracellular KYNA levels. These data demonstrate that adenosine is capable of raising extracellular KYNA in the rat striatum by interacting with postsynaptic neuronal A1 receptors. This mechanism may result in a synergism between the neurobiological effects of adenosine and KYNA.
Wu
Hui-Qiu
HQ
Maryland Psychiatric Research Center, University of Maryland, School of Medicine, Baltimore, Maryland 21228, USA.
Fuxe
Kjell
K
Schwarcz
Robert
R
D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D004333:Drug Administration Routes; D045604:Extracellular Fluid / Q000737:chemistry / Q000378:metabolism; D007263:Infusions, Parenteral; D007736:Kynurenic Acid / Q000032:analysis / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D017072:Neostriatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010627:Phenethylamines / Q000494:pharmacology; D017378:Quinolinic Acid / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043682:Receptor, Adenosine A1 / Q000187:drug effects / Q000378:metabolism*; D013806:Theophylline / Q000031:analogs & derivatives* / Q000494:pharmacology; D014851:Wakefulness
D010627:Phenethylamines; D043682:Receptor, Adenosine A1; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; C053907:8-cyclopentyl-1,3-dimethylxanthine; D013806:Theophylline; D017378:Quinolinic Acid; D007736:Kynurenic Acid; D000241:Adenosine