FOS EXPRESSION IN THE BRAIN-STEM AND CEREBELLUM FOLLOWING PHENCYCLIDINE AND MK801

The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists p hencyclidine (PCP) and dizocilpine maleate (MK801) cause nystagmus, tr emor, and cerebellar ataxia at toxic doses. We have shown that PCP but not MK801 is toxic to rat cerebellar Purkinje cells. To study the mec hanism and pathways of PCP and MK801 action, Fos protein expression wa s examined in the cerebellum and functionally related nuclei of the br ainstem. PCP, 1-50 mg/kg i.p., induced Fos immunostaining in neurons o f the inferior olive, cerebellar granule cell layer, and deep cerebell ar and vestibular nuclei. At higher doses, PCP, 25-50 mg/kg, induced d ense Fos immunoreactivity throughout the inferior olive except for ros tral parts of medial accessory olive and caudal parts of principal oli ve. At lower doses of PCP, 1-10 mg/kg, Fos positive cells in inferior olive were concentrated in the subnucleus beta. 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 Pu rkinje cells were observed adjacent to these patches. At the highest d ose of PCP tested (50 mg/kg), Fos was expressed in the fastigial, inte rpositus, and dentate nuclei, and in vestibular nuclei, most prominent ly in the medial vestibular nucleus. At lower doses, Fos was expressed mainly in medial cerebellar output nuclei and in vestibular nuclei. M K801, 0.2-10 mg/kg i.p., induced Fos expression in the same regions as PCP. However, MK801-induced Fos expression in inferior olive was loca lized primarily to subnucleus beta. No apparent differences in the num ber or distribution of Fos positive neurons were observed at MK801 dos es of 0.2-10 mg/kg. MK801 also induced Fos expression in fastigial and vestibular nuclei, but not in lateral (interpositus and dentate) cere bellar nuclei. MK801, 0.2-10 mg/kg, induced patchy Fos expression in c erebellar 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 MK801 suggests that its toxicit y to Purkinje cells is at least partially the result of excessive acti vity of climbing fibers, the excitatory neural input that arises from the inferior olive and synapses on Purkinje cell dentrities. (C) 1996 Wiley-Liss, Inc.