Inhibition by KF17837 of adenosine A2A receptor-mediated modulation of striatal GABA and ACh release.
1. The effect of the A2A adenosine receptor agonist, 2-p-(2-carboxyethyl)phenethyl-amino-5'-N-ethylcarboxamidoadenosine (CGS 21680) on the potassium evoked release of [3H]-gamma-aminobutyric acid ([3H]-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 [3H]-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 [3H]-GABA from striatal nerve terminals was unaffected by the presence of the GABA receptor antagonists, bicuculline (10 microM), phaclofen (100 microM) and 2-hydroxysaclofen (100 microM). Similarly the opioid receptor antagonist, naloxone (10 microM), the adenosine A1 receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 40 nM), and the cholinoceptor antagonists, mecamylamine (10 microM) and atropine (100 nM) had no effect on this inhibition. 3. The ability of CGS 21680 (0.1 nM) to stimulate the release of [3H]-acetylcholine ([3H]-ACh) from striatal nerve terminals was unaffected by the presence of bicuculline (10 microM), 2-hydroxysaclofen (100 microM), phaclofen (100 microM), naloxone (10 microM) and DPCPX (4 nM). 4. The novel A2A receptor antagonist, (E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine (KF 17837), blocked the CGS 21680 (1 nM)-induced inhibition of [3H]-GABA efflux with an EC50 of approximately 30 nM and also antagonized the CGS 21680 (0.1 nM)-induced stimulation of [3H]-ACh release with an EC50 of approximately 0.3 nM. 5. It is concluded that the A2A 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 [3H]-GABA release. No evidence was seen for a difference in the ligand binding sites of this receptor in the two groups of nerve terminals.
Kurokawa
M
M
Department of Pharmacology, University of Cambridge.
Kirk
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Kirkpatrick
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Kase
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Richardson
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PJ
D000109:Acetylcholine / Q000378:metabolism*; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D005917:Globus Pallidus / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D009411:Nerve Endings / Q000187:drug effects / Q000378:metabolism; D010627:Phenethylamines / Q000494:pharmacology; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017208:Rats, Wistar; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014970:Xanthines / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D000959:Antihypertensive Agents; D018756:GABA Antagonists; D008024:Ligands; D010627:Phenethylamines; D058915:Purinergic P1 Receptor Antagonists; D014970:Xanthines; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; C081198:KF 17837; D005680:gamma-Aminobutyric Acid; D000241:Adenosine; D000109:Acetylcholine