Effects of adenosine and gamma-aminobutyric acid a receptor antagonists onN-methyl-D-aspartate induced neurotoxicity in the rat hippocampus

This study investigated the modulatory actions of adenosine and gamma-amino butyric acid (GABA) on several aspects of N-methyl-D-aspartate (NMDA)-induc ed neurotoxicity, including neuronal loss, atrophy, necrosis, and calcium a ccumulation in the hippocampus. For this purpose, we combined unilateral in trahippocampal injections of NMDA (24 nmoles) with acute injections of the selective Al adenosine receptor antagonist DPCPX (0.03 pmoles), the selecti ve adenosine A2a receptor antagonist CSC (1.5 pmoles), a combination of the se two antagonists, and injections of the selective GABA A receptor antagon ist bicuculline (60 pmoles). Fifteen days after NMDA injection, neuronal lo ss with preservation of architecture was observed in stratum oriens, pyrami dale, radiatum, lacunosum-moleculare, and stratum moleculare of Ammon's hor n, and in radial and granular layers of the dentate gyrus. NMDA plus vehicl e also produced a small degree of brain tissue necrosis (holes in the struc ture) in four of five brains. Acute injections of CSC, but not DPCPX or bic uculline, significantly increased the extent of neuronal loss produced by N MDA plus vehicle. CSC in combination with NMDA induced significantly more n ecrosis than NMDA plus vehicle. A significant degree of atrophy was observe d in the hippocampus after treatment with NMDA plus vehicle, and bicucullin e significantly increased the magnitude of this atrophy. NMDA-induced calci um deposits were detected within the radiatum and lacunosum-moleculare laye rs of the hippocampus and in the hilus of the dentate, but not in the strat um oriens, stratum pyramidale, or in the granular layer of the dentate gyru s. However, treatment with the different antagonists did not significantly modify the magnitude of the NMDA-induced calcium deposits. These results re veal a selective vulnerability of certain areas of the hippocampus to the a ccumulation of calcium deposits, and a selective interaction between adenos ine receptors and NMDA-induced neurotoxicity in the hippocampus. (C) 1999 W iley-Liss, Inc.