Browsing by Subject "schizophrenia"
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Item Effects of perinatal phencyclidine treatment on neuronal viability, N-methyl-D-aspartate receptor regulation and schizophrenic-like behaviors(2009-03-06) Noelle Catherine Anastasio; Kenneth M. Johnson, Ph.D.; Kelly T. Dineley, Ph.D.; Kathryn A. Cunningham, Ph.D.; Joel P. Gallagher, Ph.D.; Geoffrey T. Swanson, Ph.D.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.Item Regional and temporal differential regulation of the N-methyl-D-aspartate receptor by phencyclidine during development(2005-07-06) Noelle Catherine Anastasio; Kenneth M. Johnson, PhD.; Kathryn Cunningham, PhD.; Giulio Taglialatela, PhD.; Geoffrey T. SwansonDisruptions in glutamatergic neurotransmission may play a role in the pathogenesis of schizophrenia. The purpose of this study was to determine phencyclidine (PCP)-induced changes in the NMDA receptor subunit composition and the relationship of these changes to the deficits in pre-pulse inhibition (PPI) caused by PCP treatment. Postnatal rats were treated with atypical or typical antipsychotics or selective dopamine or serotonin receptor antagonists prior to acute or sub-chronic PCP. This study provides evidence that two distinct mechanisms underlie effects of acute and sub-chronic PCP on NMDA receptor subunit up-regulation. Furthermore, we discovered that D1, D2, and 5-HT2A receptors play a pivotal role in sub-chronic PCP-induced up-regulation of NR1 and NR2A. Finally, we were able to correlate changes in NMDA receptor subunits to the behavioral effects of PCP in this animal model of schizophrenia.Item Role of the PI-3K/Akt and ERK pathways in phencyclidine-induced neurotoxicity in neonatal rats and the protection by lithium and BDNF(2009-06-11) Yan Xia; Kenneth M. Johnson; Xiaodong Cheng; Pramod Dash; Kelly T. Dineley; Joe GallagherPhencyclidine is an N-methyl-D-aspartate receptor (NMDAR) open channel blocker that causes schizophrenia-like symptoms in healthy humans and exacerbates psychoses in schizophrenics. In animals, PCP administration to immature rats causes wide spread neuronal death during brain development and results in behavioral deficits that resemble those observed in schizophrenic patients in later life. The purpose of this study was to investigate the mechanisms of PCP-induced neurotoxicity as well as the protection by lithium and brain-derived neurotrophic factor (BDNF). In corticostriatal slice cultures, we found that lithium and BDNF, inhibited PCP-induced caspase-3 activation and DNA fragmentation in a concentration-dependent manner, respectively. Lithium and BDNF also prevented the inhibitory action of PCP on the phosphatidylinositol-3 kinase (PI-3K)/Akt and extracellular regulated kinase (ERK) pathways and suppressed activation of the pro-apoptotic factor, glycogen synthase kinase-3â (GSK-3â), evoked by PCP. Furthermore, blocking either the PI-3K/Akt or the ERK pathway abolished the protective effects of lithium and BDNF. Western blot analysis revealed that the PI-3K/Akt and ERK pathways were stimulated by lithium and BDNF in parallel; however, inhibition of ERK and PI-3K cooperatively regulated GSK-3â activity by reducing its phosphorylation at serine 9. In vivo, acute PCP administration to rats on postnatal day (PN) 7 caused inhibition of Akt and ERK and activation of GSK-3â in the three brain regions examined (frontal cortex, striatum, and hippocampus). After the last dose of subchronic PCP administration on PN 7, 9, 11, inhibition of ERK was still found in the three regions, though it lasted for a much shorter period than after administration on PN 7 only; Inhibition of Akt was only observed in the frontal cortex; GSK-3â activity was not affected in any of the regions. Finally, subchronic PCP administration during brain development resulted in dysregulation of the PI-3K/Akt and ERK pathways upon PCP challenge in adolescence (PN 35). These studies strongly suggest that the PI-3K/Akt and ERK pathways are two important signaling transductions implicated in PCP-induced neurotoxicity in developing brains and in the protection of lithium and BDNF.