INHIBITION BY KF17837 OF ADENOSINE A(2A) RECEPTOR-MEDIATED MODULATION OF STRIATAL GABA AND ACH RELEASE

1 The effect of the A(2A) adenosine receptor agonist, 2-p-(-2-carboxyethyl)phenethyl-amino- 5'-N-ethylcarboxamidoadenosine (CGS 21680) on the potassium evoked release of [H-3]-gamma-aminobutyric acid (H-3]-GABA) from nerve terminals derived from the caudate-putamen and the globus pallidus of the rat was compared. In both preparations CGS 21680 (1 nM) inhibited the [H-3]-GABA release evoked by 15 mM KCl but had no effect on that evoked by 30 mM KCl. 2 The ability of CGS 21680 (1 nM) to inhibit the release of [H-3]-GABA from striatal nerve terminals was unaffected by the presence sf the GABA receptor antagonists, bicuculline (10 mu M), phaclofen (100 mu M) and 2-hydroxysaclofen (100 mu M). Similarly the opioid receptor antagonist, naloxone (10 mu M), the adenosine A(1) receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 40 nM), and the cholinoceptor antagonists, mecamylamine (10 mu M) and atropine (100 nM) had no effect on this inhibition. 3 The ability of CGS 21680 (0.1 nM) to stimulate the release of [H-3]-acetylcholine [H-3]-ACh from striatal nerve terminals was unaffected by the presence of bicuculline (10 mu M), 2-hydroxysaclofen (100 mu M), phaclofen (100 mu M), naloxone (10 mu M) and DPCPX (4 nM). 4 The novel A(2A) receptor antagonist, (E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine (KF 17837), blocked the CGS 21680 (1 nM)-induced inhibition of [H-3]-GABA efflux with an EC(50) Of approximately 30 nM and also antagonized the CGS 21680 (0.1 nM)-induced stimulation of [H-3]-ACh release with an EC(50) of approximately 0.3 nM. 5 It is concluded that the A(2A) adenosine receptor is present on both GABAergic and cholinergic nerve terminals of the rat striatum and that in both the caudate-putamen and the globus pallidus this receptor inhibits [H-3]-GABA release. No evidence was seen for a difference in the ligand binding sites of this receptor in the two groups of nerve terminals.