Long-term effects of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionateand 6-nitro-7-sulphamoylbenzo(f)quinoxalinedione-2,3-dione in the rat basal ganglia: Calcification, changes in glutamate receptors and glial reactions

Previous data from our laboratory indicate that 25 mM ibotenic acid induces intracellular calcifications in the rat basal forebrain. Because of the la ck of specificity of ibotenic acid for a glutamate receptor subtype, a dose -response study with alpha-amino-3-hydroxy 5-methyl-4-isoxazole propionate was undertaken and calcified areas (identified with Alizarin Red staining) as well as astro- and microglial reactions (by autoradiography with [H-3]la zabemide and [H-3]Ro 5-4864) were quantified at one month postlesion, alpha -Amino-3-hydroxy-5-methyl-4-isoxazole propionate administered into the glob us pallidus induced, in a dose-dependent manner, the formation of calcium d eposits and the activation of both glial cells, the microglial reaction bei ng particularly robust. From this study, a dose of 5.4 mM alpha-amino-3-hyd roxy-5-methyl-4-isoxazole propionate was selected for further experiments. [H-3]alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate, [H-3]dizocilpin e maleate and [H-3]PN 200-110 binding in vitro were performed to assess aut oradiographically whether the tissue damage was associated with changes in glutamate receptors and calcium channel binding sites. In the alpha-amino-3 -hydroxy-5-methyl-4-isoxazole propionate-treated animals, the specific bind ing of [H-3]alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate was signi ficantly reduced by 28% in the lesioned ventral pallidum, whereas it was un changed in the globus pallidus and substantia innominata. In these three nu clei, calcifications developed and an increase in both glial markers was me asured. In contrast, the binding of [H-3]PN 200-110 and [H-3]dizocilpine ma leate were unaffected. Co-injection of 15 mM 6-nitro-7-sulphamoylbenzo(f)qu inoxaline-2,3-dione, selective alpha-amino-3-hydroxy-5-methyl-4-isoxazole p ropionate/kainate receptor antagonist, prevented the formation of calcium c oncretions, the microglial reaction and the decrease in [H-3]alpha-amino-3- hydroxy-5-methyl-4-isoxazole propionate binding but it failed to inhibit to tally the astroglial reaction induced by alpha-amino-3-hydroxy-5-methyl-4-i soxazole propionate. This may suggest that the microglial reaction and calc ification take place through different mechanisms from the astrogliosis ass ociated with the neuronal loss. In conclusion, acute administration of alpha-amino-3-hydroxy-5-methyl-4-iso xazole propionate in the rat globus pallidus elicits a dose-dependent calci fication process associated with a chronic reaction of astrocytes and micro glia. alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate-induced injury is accompanied by a slight reduction of alpha-amino-3-hydroxy-5-methyl-4-is oxazole propionate receptors in the ventral pallidum, whereas the binding o f N-methyl-D-aspartate and L-type calcium channels receptors remains unchan ged in any lesioned nucleus. (C) 1999 IBRO. Published by Elsevier Science L td.