1. In order to investigate the modulatory effects of
adenosine on
excitatory amino acid projections onto striatal medium spiny neurons, whole-cell patch clamp experiments were carried out in rat brain slices. The effects of various agonists for P1 (
adenosine) and P2 (
ATP)
purinoceptors and their antagonists were investigated. The A2A receptor agonist 2-p-(2-carboxyethyl)phenythylamino-5'-N-ethylcarboxamidoadenosine (
CGS 21680; 0.1 microM), the A1 receptor agonist 2-chloro-N6-cyclcopentyladenosine (CCPA; 10 microM) and the non-selective
P1 purinoceptor antagonist 8-(p sulphophenyl)-theophylline (8-SPT; 100 microM) did not alter the resting membrane potential, the threshold current necessary to elicit an action potential, the amplitude of spikes, their rise time, the amplitude of the afterhyperpolarization (AHP) and the time to peak of the AHP. 2.
N-methyl-D-aspartate (
NMDA; 1-1000 microM) caused a concentration-dependent inward current which was larger in the absence than in the presence of Mg2+ (1.3 mM). In a subset of striatal neurones, the current response to
NMDA (10 microM) and the accompanying increase in conductance were both inhibited by
CGS 21680 (0.01-1 microM). The effect of
CGS 21680 (0.1 microM) persisted in the presence of
tetrodotoxin (0.5 microM) or in a Ca(2+)-free medium, under conditions when synaptically mediated influences may be negligible. 3. The A3 receptor agonist N6-2-(4-aminophenyl)ethyladenosine (
APNEA; 0.1-10 microM) also diminished the effect of
NMDA (10 microM), while the A1 receptor agonists CCPA (0.1-10 microM) and (2S)-N6-[2-endonorbornyl]
adenosine [
S(-)-ENBA; 10 microM] as well as the endogenous, non-selective
P1 purinoceptor agonist
adenosine (100 microM) were inactive. The endogenous non-selective
P2 purinoceptor agonist
ATP (1000 microM) also failed to alter the current response to
NMDA (10 microM).
Adenosine (100 microM), but not
ATP (1000 microM) became inhibitory after blockade of
nucleoside uptake by S[4-nitrobenzyl)-6-thioguanosine (NBTG; 30 microM). 4. 8-(p-Sulphophenyl)-
theophylline (8-SPT; 100 microM), as well as the A2A receptor antagonist 8-(3-chlorostyryl)
caffeine (CSC; 1 microM) and the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (
DPCPX) at 0.03, but not 0.003 microM abolished the inhibitory action of CGS 21,680 (0.1 microM). None of these compounds altered the effect of
NMDA (10 microM) by itself.
DPCPX (0.03 microM) prevented the inhibition of
APNEA (10 microM). 5. There was no effect of CGS 21,680 (0.1 microM), when guanosine 5'-O-(3-thiodiphosphate (
GDP-beta-S; 300 microM) was included in the pipette
solution in order to block
G protein-mediated reactions. 6. In conclusion,
adenosine receptors, probably of the A2A-subtype, inhibit the conductance of
NMDA receptor channels in a subset of medium spiny neurones of the rat striatum by a transduction mechanism which involves a
G protein.