CEREBELLAR TOXICITY OF PHENCYCLIDINE

Phencyclidine (PCP), dizocilpine maleate (MK801), and other NMDA antag onists are toxic to neurons in the posterior cingulate and retrospleni al cortex. To determine if additional neurons are damaged, the distrib ution of microglial activation and 70 kDa heat shock protein (HSP70) i nduction was studied following the administration of PCP and MK801 to rats, PCP (10-50 mg/kg) induced microglial activation and neuronal HSP 70 mRNA and protein expression in the posterior cingulate and retrospl enial cortex. In addition, coronal sections of the cerebellar vermis o f PCP (50 mg/kg) treated rats contained vertical stripes of activated microglial in the molecular layer. In the sagittal plane, the microgli al activation occurred in irregularly shaped patches, suggesting damag e to Purkinje cells. In accord with this finding, PCP induced HSP70 pr otein and mRNA expression in Purkinje cells, Although there were relat ively few foci of microglial activation and cells with HSP70 protein i nduction, HSP70 mRNA was detected in many Purkinje cells located throu ghout the cerebellar hemispheres as well as the vermis. MK801, at dose s of 5-10 mg/kg, induced microglial activation and neuronal HSP70 mRNA and protein expression in the cingulate and retrosplenial cortex but not in the cerebellum. At the dose of 1 mg/kg MK801 induced HSP70 but did not consistently activate microglia. These data suggest that micro glia are activated by MK801 doses that kill or severely damage neurons , whereas HSP70 is induced in ''stressed'' neurons at MK801 doses well below those that produce severe neurotoxicity. These observations sug gest that PCP, but not MK801, is toxic to Purkinje cells and raise the question of whether NMDA antagonists or sigma ligands other than PCP are toxic to the cerebellum. Moreover, this study illustrates the usef ulness of microglial activation and HSP70 induction as markers of neur otoxicity.