Nitric oxide, a gaseous inter- and intracellular messenger, is thought to mediate neurotoxicity via excitatory amino acid receptors which may contribute to the pathogenesis of a variety of neuronal diseases. Excitotoxin lesions induced by quinolinic acid were made unilaterally in the rat striatum to study biochemically, light- and electron microscopically the possible involvement of the nitric oxide synthesizing enzyme nitric oxide synthase in degeneration processes. 5 days after quinolinic acid injection nitric oxide synthase activity in the striatum was elevated to 196.5% (P < 0.005% as compared to controls). There was no requirement of Ca2+ for the enzyme activity measured indicating that the elevation is due to the inducible isoform of nitric oxide synthase. Parallel to the depletion of neurons by quinolinic acid a massive gliosis was seen. Whereas quiescent astroglial cells in the normal striatum did not show any light microscopically detectable nicotinamide adenine dinucleotide phosphate diaphorase reaction, reactive astroglia revealed a substantial labeling distributed over the cell body and their stellar processes. Within the lesion and, particularly, close to the needle tract the number of microglia/macrophages labeled by isolectin B4 increased dramatically. Reactive microglial cells macrophages, situated along the needle tract and characterized by a pseudopodic or a globular shape, contained highest staining activity. At the ultrastructural level only disintegrated, if any, neuronal perikarya were seen five days after quinolinic acid injection while numerous reactive glial cells were observed. Reactive astroglia showed nicotinamide adenine dinucleotide phosphate diaphorase activity by displaying a substantial labeling of the nuclear envelope and endoplasmic membranes. Occasionally stained mitochondria were encountered. Globular-shaped (ameboidal) microglia near the needle tract were rich in phagocytotic debris and, apart from formazan-positive endomembranes, their plasmalemma was often nicotinamide adenine dinucleotide phosphate diaphorase stained. Additionally, in those cells regions of highly electron-dense puncta were seen which differ sharply from other cytoplasmic areas. Such sand-like accumulations of nicotinamide adenine dinucleotide phosphate diaphorase positive grains have never been observed in other cell types, indicating a special type of nitric oxide synthase representation, possibly that of the inducible isoform.