ADENOSINE A(2A) RECEPTORS INHIBIT THE CONDUCTANCE OF NMDA RECEPTOR CHANNELS IN RAT NEOSTRIATAL NEURONS

Whole-cell patch clamp experiments were carried out in rat striatal br ain slices. In a subset of striatal neurons (70-80%), NMDA-induced inw ard currents were inhibited by the adenosine A(2A) receptor selective agonist CGS 21680. The non-selective adenosine receptor antagonist 8-( p-sulphophenyl)-theophylline and the A(2A) receptor selective antagoni st 8-(3-chlorostyryl)caffeine abolished the inhibitory action of CGS 2 1680. Intracellular GDP-beta-S, which is known to prevent G protein-me diated reactions, also eliminated the effect of CGS 21680. Extracellul ar dibutyryl cAMP, a membrane permeable analogue of cAMP, and intracel lular Sp-cAMPS, an activator of cAMP-dependent protein kinases (PKA), both abolished the CGS 21680-induced inhibition. By contrast, Rp-cAMPS and PKI 14-24 amide, two inhibitors of PKA had no effect. Intracellul ar U-73122 (a phospholipase C inhibitor) and heparin (an inositoltriph osphate antagonist) prevented the effect of CGS 21680. Finally, a more efficient buffering of intracellular Ca2+ by a substitution of EGTA ( 11 mM) by BAPTA (5.5 mM) acted like U-73122 or heparin. Hence, A(2A) r eceptors appear to negatively modulate NMDA receptor channel conductan ce via the phospholipase C/inositoltriphosphate/Ca2+ pathway rather th an the adenylate cyclase/PKA pathway.