Adenosine A 2A receptors are abundant in the caudate-putamen and involved in the motor control in several species. In MPTP-treated monkeys, A 2A receptor-blockade with an antagonist alleviates parkinsonian symptoms without provoking dyskinesia, suggesting this receptor may offer a new target for the antisymptomatic therapy of Parkinson's disease. In the present study, a signi®cant neuroprotective effect of A 2A receptor antagonists is shown in experimental models of Parkinson's disease. Oral administration of A 2A receptor antagonists protected against the loss of nigral dopaminergic neuronal cells induced by 6-hydroxydopamine in rats. A 2A antagonists also prevented the functional loss of dopaminergic nerve terminals in the striatum and the ensuing gliosis caused by MPTP in mice. The neuroprotective property of A 2A receptor antagonists may be exerted by altering the packaging of these neurotoxins into vesicles, thus reducing their effective intracellular concentration. We therefore conclude that the adenosine A 2A receptor may provide a novel target for the long-term medication of Parkinson's disease, because blockade of this receptor exerts both acutely antisymptomatic and chronically neuroprotective activities.

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1The effect of the A2A adenosine receptor agonist, 2-p-(-2-carboxyethyl)phenethyl-amino-5'-Nethylcarboxamidoadenosine (CGS 21680) on the potassium evoked release of [3H]-y-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 KCI 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 gM), phaclofen (1001iM) and 2-hydroxysaclofen (100ZtM). Similarly the opioid receptor antagonist, naloxone (10 fiM), the adenosine Al receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 40 nM), and the cholinoceptor antagonists, mecamylamine (10 lM) and atropine (100 nM) had no effect on this inhibition. 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.