title: Characteristics of GABA release induced by free radicals in mouse hippocampal slices.
abstract: The release of the inhibitory neurotransmitter GABA is generally enhanced under potentially cell-damaging conditions. The properties and regulation of preloaded [3H]GABA release from mouse hippocampal slices were now studied in free radical-containing medium in a superfusion system. Free radical production was induced by 0.01% of H2O2 in the medium. H2O2 markedly potentiated GABA release, which was further enhanced about 1.5-fold by K+ stimulation (50 mM). In Ca2+-free media this stimulation was not altered, indicating that the release was mostly Ca2+-independent. Moreover, omission of Na+ increased the release, suggesting that it is mediated by Na+-dependent transporters operating outwards, a conception confirmed by the enhancement with GABA homoexchange. Inhibition of the release with the ion channel inhibitors diisothiocyanostilbene-2,2'-disulphonate and 4-acetamido-4'-isothiocyanostilbene-2,2'-disulphonate indicates that Cl(-) channels also participate in the process. This release was not modified by the adenosine receptor (A1 and A2a) agonists and ionotropic glutamate receptor agonists kainate, N-methy-D: -aspartate and 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate, whereas the agonists of metabotropic glutamate receptors of group I [(S)-3,5-dihydroxyphenylglycine] and of group II [(2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate] enhanced it by receptor-mediated mechanisms, the effects being abolished by their respective antagonists. The group III agonist L+-2-amino-4-phosphonobutyrate reduced the evoked GABA release, but this was not affected by the antagonist. Furthermore, the release was reduced by activation of protein kinase C by 4 beta-phorbol 12-myristate 13-acetate and by inhibition of tyrosine kinase by genistein and of phoshoplipase by quinacrine. On the other hand, increasing cGMP levels with the phosphodiesterase inhibitor zaprinast, selective for PDE5, 6 and 9, and NO production with the NO-generating compounds hydroxylamine, sodium nitroprusside and S-nitroso-N-penicillamine enhanced the release. The regulation of GABA release induced by free radical production proved thus to be rather complex. Under potentially cell-damaging conditions, the potentiation of GABA release may be a mechanism to counteract hyperactivity and reduce the effects of excitatory amino acid release. On the other hand, reduction of GABA release could be harmful and contribute to excitotoxic damage and neuronal degeneration.
authors: Tampere Brain Research Center, Medical School, University of Tampere, Tampere 33014, Finland. blpisa@uta.fi
authors: Pirjo
authors: P
authors: Saransaari
authors: Simo S
authors: SS
authors: Oja
mesh_terms: D058907:Adenosine A1 Receptor Agonists; D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D002118:Calcium / Q000378:metabolism; D018118:Chloride Channels / Q000187:drug effects / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005609:Free Radicals / Q000494:pharmacology*; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D051379:Mice; D011493:Protein Kinase C / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D017470:Receptors, Glutamate / Q000187:drug effects; D015290:Second Messenger Systems; D012964:Sodium / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D058907:Adenosine A1 Receptor Agonists; D058908:Adenosine A2 Receptor Agonists; D018118:Chloride Channels; D002712:Chlorides; D005609:Free Radicals; D018755:GABA Agonists; D018756:GABA Antagonists; D017470:Receptors, Glutamate; D026941:Sodium Channel Blockers; D005680:gamma-Aminobutyric Acid; D012964:Sodium; D006861:Hydrogen Peroxide; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D002118:Calcium
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