Effects of perinatal phencyclidine treatment on neuronal viability, N-methyl-D-aspartate receptor regulation and schizophrenic-like behaviors

Clinical use of phencyclidine (PCP), a potent dissociative anesthetic, was abandoned as a result of reports of post-operative hallucinations and disoriented behavior; further, 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 NMDA receptor (NMDAR) antagonist. Administration to immature rats has been shown to cause neurotoxicity in a regional and treatment dependent manner and development of schizophrenic-like behaviors later in life. 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 if there is a causal relationship between cell death and the development of aberrant behaviors in perinatal rats. The first specific aim 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. Specific aim 2 is designed to determine the functionality of the cortical NMDAR following both acute and sub-chronic PCP treatment by assessing NMDA- and glycine-dependent activation of 3H-MK-801 binding. The subunit composition of the NMDAR that mediates PCP-induced neuronal neurotoxicity is currently unknown; therefore, we designed specific aim 3 to show that the synaptic or extrasynaptic localization of NMDA NR2A and 2B receptors may dictate function and neuronal susceptibility to cell death. Finally, the purpose of specific aim 4 is to demonstrate that neurotoxicity underlies the development of behaviors which model several aspects of schizophrenia, including the positive symptoms (locomotor sensitization), the negative symptoms (social interaction and social discrimination) and deficits in sensorimotor gating (PPI of acoustic startle). Work within this dissertation discovered that PCP induces neurotoxicity in developing pups in a manner that is highly regulated affecting the distribution, composition, number, and function of NMDAR and that this loss of cortical neurons and altered cortical landscape is associated with behavioral deficits that are similar to both the positive and negative symptoms of schizophrenia.