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Adenosine A 2A receptor blockade differentially influences excitotoxic mechanisms at pre‐ and postsynaptic sites in the rat striatum
Author(s) -
Tebano Maria Teresa,
Pintor Annita,
Frank Claudio,
Domenici Maria Rosaria,
Martire Alberto,
Pepponi Rita,
Potenza Rosa Luisa,
Grieco Rosa,
Popoli Patrizia
Publication year - 2004
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.20138
Subject(s) - nmda receptor , excitotoxicity , glutamate receptor , neuroprotection , chemistry , pharmacology , adenosine a2a receptor , agonist , neurotransmitter , postsynaptic potential , adenosine receptor , medicine , biology , receptor , biochemistry
Adenosine A 2A receptor antagonists are being regarded as potential neuroprotective drugs, although the mechanisms underlying their effects need to be better studied. The aim of this work was to investigate further the mechanism of the neuroprotective action of A 2A receptor antagonists in models of pre‐ and postsynaptic excitotoxicity. In microdialysis studies, the intrastriatal perfusion of the A 2A receptor antagonist ZM 241385 (5 and 50 nM) significantly reduced, in an inversely dose‐dependent way, the raise in glutamate outflow induced by 5 mM quinolinic acid (QA). In rat corticostriatal slices, ZM 241385 (30–100 nM) significantly reduced 4‐aminopyridine (4‐AP)‐induced paired‐pulse inhibition (PPI; an index of neurotransmitter release), whereas it worsened the depression of field potential amplitude elicited by N ‐methyl‐ D ‐aspartate (NMDA; 12.5 and 50 μM). The A 2A antagonist SCH 58261 (30 nM) mimicked the effects of ZM 241385, whereas the A 2A agonist CGS 21680 (100 nM) showed a protective influence toward 50 μM NMDA. In rat striatal neurons, 50 nM ZM 241385 did not affect the increase in [Ca 2+ ] i or the release of lactate dehydrogenase (LDH) induced by 100 and 300 μM NMDA, respectively. The ability of ZM 241385 to prevent QA‐induced glutamate outflow and 4‐AP‐induced effects confirms that A 2A receptor antagonists have inhibitory effects on neurotransmitter release, whereas the results obtained toward NMDA‐induced effects suggest that A 2A receptor blockade does not reduce, or even amplifies, excitotoxic mechanisms due to direct NMDA receptor stimulation. This indicates that the neuroprotective potential of A 2A antagonists may be evident mainly in models of neurodegeneration in which presynaptic mechanisms play a major role. © 2004 Wiley‐Liss, Inc.