Role of NMDAR Regulation in Phencyclidine-Induced Neurotoxicity

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DESCRIPTION (provided by applicant): Clinical use of phencyclidine (PCP), a potent dissociative anesthetic, was abandoned because of reports of post-operative hallucinations and disoriented behavior. Due to its hallucinogenic effects, PCP appeared on the drug of abuse scene in the mid-1960's known as "angel dust" but its illicit use has substantially diminished because of its psychotomimetic properties. PCP intoxication in humans has also been shown to mimic both the positive and negative symptoms of schizophrenia as well as exacerbate psychoses in schizophrenics. PCP elicits its major actions as a noncompetitive NMDAR antagonist, a member of the ionotropic glutamate family of receptors. PCP administration in immature rats has been shown to cause.. neurotoxicity and later in development, aberrant behaviors. Preliminary experiments have shown that two distinct mechanisms of receptor trafficking and protein synthesis are likely involved in the differences in NMDAR up-regulation that exist between perinatal acute and sub-chronic PCP administration and that this may underlie regional- and dosage-dependent differences in the mechanism of PCP-induced neurotoxicity. The purpose of this study is to determine the mechanism and functional consequences of PCP-induced regulation of the NMDAR in association with neurotoxicity in the frontal cortex and striatum in perinatal rats. The specific aims of this project will focus on delineating the mechanisms of regulation of the NMDAR, specifically the role of synthesis and trafficking of the receptor following acute and sub-chronic PCP administration through the use of selective inhibitors of synthesis and trafficking pathways and analysis via Western blot. In addition, we plan to investigate the role of indirect activation of DA and 5-HT receptors on the NMDAR using 3H-MK-801 binding. Finally, in order to relate regulation and function of the NMDAR to NMDA-mediated cell death, we plan to incorporate double-labeled immunohistochemistry of the NR1 and NR2A/B subunits and a known marker of neurotoxicity, cleaved caspase-3. Lay Summary: PCP, also known as "angel dust", is a powerful psychoactive substance that is mainly abused in urban regions of several large cities in the United States. It elicits its actions through blockade of the NMDA receptor in brain regions responsible for memory, emotions, and higher thought processes. This project aims to further clarify the actions of PCP at the NMDA receptor in order to gain insight into the mechanisms underlying its hallucinogenic, psychotomimetic, and neurotoxic properties.