The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists phencyclidine (PCP) and dizocilpine maleate (MK801) cause nystagmus, tremor, and cerebellar ataxia at toxic doses. We have shown that PCP but not MKSOl is toxic to rat cerebellar Purkinje cells. To study the mechanism and pathways of PCP and MK801 action, Fos protein expression was examined in the cerebellum and functionally related nuclei of the brainstem. PCP, 1-50 mg/kg i.p., induced Fos immunostaining in neurons of the inferior olive, cerebellar granule cell layer, and deep cerebellar and vestibular nuclei. At higher doses, PCP, 25-50 mg/kg, induced dense Fos immunoreactivity throughout the inferior olive except for rostra1 parts of medial accessory olive and caudal parts of principal olive. At lower doses of PCP, 1-10 mg/kg, Fos positive cells in inferior olive were concentrated in the subnucleus p. In the cerebellum Fos positive granule cells were arranged in patches distributed throughout the cerebellar cortex following PCP, 1-50 mg/kg. Rare Fos positive Purkinje cells were observed adjacent to these patches. At the highest dose of PCP tested (50 mg/kg), Fos was expressed in the fastigial, interpositus, and dentate nuclei, and in vestibular nuclei, most prominently in the medial vestibular nucleus. At lower doses, Fos was expressed mainly in medial cerebellar output nuclei and in vestibular nuclei. MKSO1, 02-10 mg/kg i.p., induced Fos expression in the same regions as PCP. However, MK801induced Fos expression in inferior olive was localized primarily to subnucleus p. No apparent differences in the number or distribution of Fos positive neurons were observed at MK801 doses of 02-10 mg/kg. MKSOl also induced Fos expression in fastigial and vestibular nuclei, but not in lateral (interpositus and dentate) cerebellar nuclei. MKSOl, 02-10 mg/kg, induced patchy Fos expression in cerebellar granule cells that was similar to PCP. These results support our earlier observations that PCP and MK801 have different actions in the cerebellum, although they both cause ataxia and indistinguishable behavioral symptoms. That high doses of PCP induce substantially more Fos expression in inferior olive than MKSOl suggests that its toxicity to Purkinje cells is at least partially the result of excessive activity of climbing fibers, the excitatory neural input that arises from the inferior olive and synapses on Purkinje cell dentrities.