Mature organotypic cultures of rat corticostriatal system (CXCA cultures) or caudate nucleus (CA cultures) were chronically exposed to 100 nM quinolinic acid (QUIN) for up to 7 weeks. Light and electron microscopic analysis showed no pathological changes in QUIN-exposed CA cultures or in control cultures incubated in regular feeding medium for this time period. In contrast, in CXCA cultures exposed to QUIN, there was focal degeneration characterized by the presence of vacuoles in neuropil, swollen dendrites, occasional swollen post-synaptic elements and degenerated neurons. Prolonged exposure to only slightly hyper-physiological concentrations of QUIN may cause neuronal death in slowly progressive neurodegenerative disorders such as Huntington's disease (HD).