EFFECT OF ADENOSINE AND SOME OF ITS STRUCTURAL ANALOGS ON THE CONDUCTANCE OF NMDA RECEPTOR CHANNELS IN A SUBSET OF RAT NEOSTRIATAL NEURONS

1 In order to investigate the modulatory effects of adenosine on excit atory amino acid projections onto striatal medium spiny neurones, whol e-cell patch clamp experiments were carried out in rat brain slices. T he effects of various agonists for P1 (adenosine) and P2 (ATP) purinoc eptors and their antagonists were investigated. The A(2A) receptor ago nist thyl)phenethylamino-5'-N-ethylcarbaxamidoadenosine (CGS 21680; 0. 1 mu M), the A(1) receptor agonist 2-chloro-N-6-cyclopentyladenosine ( CCPA; 10 mu M) and the non-selective P1 purinoceptor antagonist 8-(p-s ulphophenyl)-theophylline (8-SPT; 100 mu M) did not alter the resting membrane potential, the threshold current necessary to elicit an actio n potential, the amplitude of spikes, their rise time, the amplitude o f the afterhyperpolarization (AHP) and the time to peak of the AHP. 2 N-methyl-D-aspartate (NMDA; 1-1000 mu M) caused a concentration-depend ent inward current which was larger in the absence than in the presenc e of Mg2+ (1.3 mM). In a subset of striatal neurones, the current resp onse to NMDA (10 mu M) and the accompanying increase in conductance we re both inhibited by CGS 21680 (0.01-1 mu m). The effect of CGS 21680 (0.1 mu M) persisted in the presence of tetrodotoxin (0.5 mu M) or in a Ca2+-free medium, under conditions when synaptically mediated influe nces may be negligible. 3 The A(3) receptor agonist N-6-2-(4-aminophen yl)ethyladenosine (APNEA; 0.1-10 )mu M) also diminished the effect of NMDA (10 mu M), while the A(1) receptor agonists CCPA (0.01-10 mu M) a nd (2S)-N-6-[2-endonorbornyl]adenosine [S(-)-ENBA; 10 mu M] as well as the endogenous, non-selective P1 purinoceptor agonist adenosine (100 mu M) were inactive. The endogenous non-selective P2 purinoceptor agon ist ATP (1000 mu M) also failed to alter the current response to NMDA (10 mu M). Adenosine (100 mu M), but not ATP (1000 mu M) became inhibi tory after blockade of nucleoside uptake by S(4-nitrobenzyl)-6-thiogua nosine (NBTG; 30 mu M). 4 8-(p-Sulphophenyl)-theophylline (8-SPT; 100 mu M), as well as the A(2A) receptor antagonist 8-(3-chlorostyryl)caff eine (CSC; 1 mu M) and the A(1) receptor antagonist 8-cyclopentyl-1,3- dipropylxanthine (DPCPX) at 0.03, but not 0.003 mu M abolished the inh ibitory action of CGS 21680 (0.1 mu M). None of these compounds altere d the effect of NMDA (10 mu M) by itself. DPCPX (0.03 mu M) prevented the inhibition by APNEA (10 mu M). 5 There was no effect of CGS 21680 (0.1 mu M), when guanosine 5'-O-(3-thiodiphosphate (GDP-beta-S; 300 mu M) was included in the pipette solution in order to block G protein-m ediated reactions. 6 In conclusion, adenosine receptors, probably of t he A(2A)-subtype, inhibit the conductance of NMDA receptor channels in a subset of medium spiny neurones of the rat striatum by a transducti on mechanism which involves a G protein.