Cerebellar toxicity of phencyclidine

Area of Science:

• Neuroscience
• Toxicology
• Cellular Biology

Background:

• NMDA receptor antagonists, including Phencyclidine (PCP) and dizocilpine maleate (MK801), are known to cause neuronal toxicity.
• Previous studies indicate toxicity in the posterior cingulate and retrosplenial cortex, but the full extent of neuronal damage by these antagonists remains under investigation.

Purpose of the Study:

• To investigate the distribution of microglial activation and heat shock protein 70 (HSP70) induction following administration of PCP and MK801 in rats.
• To determine if these markers can identify additional neurotoxic effects beyond known targets of NMDA antagonists.

Main Methods:

• Rats were administered varying doses of PCP (10-50 mg/kg) and MK801 (1-10 mg/kg).
• Immunohistochemistry and mRNA analysis were used to detect microglial activation and HSP70 expression in various brain regions, including the cortex and cerebellum.
• Coronal and sagittal brain sections were analyzed to map the spatial distribution of cellular responses.

Main Results:

• PCP induced microglial activation and HSP70 expression in the posterior cingulate and retrosplenial cortex, and notably, in cerebellar Purkinje cells.
• MK801 induced microglial activation and HSP70 expression in the cortex but not the cerebellum at the tested doses.
• HSP70 induction occurred at lower MK801 doses than microglial activation, suggesting it marks neuronal stress preceding severe damage.

Conclusions:

• PCP exhibits toxicity to cerebellar Purkinje cells, a finding not observed with MK801.
• Microglial activation and HSP70 induction serve as valuable markers for detecting neurotoxicity induced by NMDA antagonists.
• The study raises questions about the cerebellar toxicity of other NMDA antagonists and sigma ligands.