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Although excitotoxic injury is thought to play a role in many pathologic conditions, the type of cell death induced by excitotoxins in vivo and the basis for the differential vulnerability of neurons to excitotoxic injury are still poorly understood. Morphologic alterations and the presence of DNA damage were examined in adult rat striatum after an intrastriatal injection of low doses of quinolinic acid, a N-methyl-D-aspartate receptor agonist. Rats were killed 6, 8, 10, or 12 hours after quinolinate or vehicle injection. Numerous neurons with necrotic morphologies were detected in the quinolinate-injected striata. In addition, few neurons with apoptotic morphologies were found in the dorsomedial striatum. DNA strand breaks were detected in tissue sections by in situ nick translation with (35)S-radiolabeled nucleotides and emulsion autoradiography. Labeled cells were first detected outside the needle track 10 hours after quinolinate injection and, on average, 20% of neurons exhibited DNA damage by 12 hours after surgery. DNA damage was found in cells with both apoptotic and necrotic morphologies. A marked differential vulnerability to DNA damage at this time was observed in two striatal compartments, the striosomes, identified as regions of dense [(3)H]naloxone binding, and the extrastriosomal matrix: the great majority of labeled cells were found in the extrastriosomal matrix and extremely few were seen in the striosomes. This preferential distribution was not due to premature cell death in the striosomes which contained numerous unlabeled neurons. The results suggest a greater vulnerability of neurons in the matrix, versus the striosomes, to early excitotoxin-induced DNA damage in rat striatum., (Copyright 1999 Wiley-Liss, Inc.)