NMDA receptor hypofunction model of schizophrenia

Olney, John W.; Newcomer, John W.; Farber, Nuri B.

doi:10.1016/s0022-3956(99)00029-1

Cited by 928 publications

(635 citation statements)

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“…71,72 Although decreased protein synthesis and compromised PTMs might generally be associated with older age, 73 matching of subjects and correction of age effects in this study indicate that this is an effect related to schizophrenia rather than age per se. Thus, the present findings support the hypothesis of diminished excitatory glutamate signaling in schizophrenia 74 brought about by abnormally expressed PSD proteins.…”

Section: Discussionsupporting

confidence: 90%

Changes in NMDA receptor subunits and interacting PSD proteins in dorsolateral prefrontal and anterior cingulate cortex indicate abnormal regional expression in schizophrenia

et al. 2006

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Abnormal expression of the N-Methyl-D-Aspartate (NMDA) receptor and its interacting molecules of the postsynaptic density (PSD) are thought to be involved in the pathophysiology of schizophrenia. Frontal regions of neocortex including dorsolateral prefrontal (DLPFC) and anterior cingulate cortex (ACC) are essential for cognitive and behavioral functions that are affected in schizophrenia. In this study, we have measured protein expression of two alternatively spliced isoforms of the NR1 subunit (NR1 C2 and NR1 C2 0 ) as well as expression of the NR2A-D subunits of the NMDA receptor in DLPFC and ACC in post-mortem samples from elderly schizophrenic patients and a comparison group. We found significantly increased expression of NR1 C2 0 but not of NR1 C2 in ACC, suggesting altered NMDA receptor cell membrane expression in this cortical area. We did not find significant changes in the expression of either of the NR1 isoforms in DLPFC. We did not detect changes of any of the NR2 subunits studied in either cortical area. In addition, we studied expression of the NMDAinteracting PSD molecules NF-L, SAP102, PSD-95 and PSD-93 in ACC and DLPFC at both transcriptional and translational levels. We found significant changes in the expression of NF-L in DLPFC, and PSD-95 and PSD-93 in ACC; increased transcript expression was associated with decreased protein expression, suggesting abnormal translation and/or accelerated protein degradation of these molecules in schizophrenia. Our findings suggest abnormal regional processing of the NMDA receptor and its associated PSD molecules, possibly involving transcription, translation, trafficking and protein stability in cortical areas in schizophrenia.

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Section: Discussionsupporting

confidence: 90%

Changes in NMDA receptor subunits and interacting PSD proteins in dorsolateral prefrontal and anterior cingulate cortex indicate abnormal regional expression in schizophrenia

et al. 2006

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“…Interestingly, the same authors and others reported that chronic PCP treatment over 3-14 days causes irreversible necrotic toxicity and apoptosis that spreads to many corticolimbic brain regions (eg the amygdala, dentate gyrus, entorhinal cortex, olfactory tubercle, and piriform cortex; Ellison and Switzer, 1993;Ellison, 1994;Corso et al, 1997;Johnson et al, 1998;Phillips et al, 2001;Sharp et al, 2001). These effects of PCP are blocked by antipsychotic drugs (Sharp et al, 1992;Johnson et al, 1998;Olney et al, 1999). No changes in absolute serotonin or dopamine concentrations have been reported with either acute or chronic treatment using high doses of PCP suggesting that there are no neurochemical lesions of these two important neurotransmitter innervations likely to be involved in the rewarding/ dysphoric actions of PCP (Jentsch et al, 1997b;Noda et al, 2000;Balla et al, 2001).…”

Section: Discussionmentioning

confidence: 95%

“…Thus, one cannot exclude the possibility that the behavioral perturbations observed here with the chronic 15 or 20 mg/kg/day PCP treatment might be related to the neurotoxic effects of PCP. Acute bolus injection of high PCP doses (50 mg/kg) produced morphological changes involving a reversible vacuole reaction affecting cytoplasmic organelles in specific neurons of the posterior cingulate and retrosplenial cortex (Olney et al, 1999). Although the acute PCP doses used in the present study were not as high (5 and 10 mg/kg), it is intriguing to note that the time of appearance of the vacuolizations (4-12 h; Olney et al, 1999) closely corresponds to the times at which elevations in brain reward threshold were observed after the acute PCP doses.…”

Section: Discussionmentioning

confidence: 99%

“…Acute bolus injection of high PCP doses (50 mg/kg) produced morphological changes involving a reversible vacuole reaction affecting cytoplasmic organelles in specific neurons of the posterior cingulate and retrosplenial cortex (Olney et al, 1999). Although the acute PCP doses used in the present study were not as high (5 and 10 mg/kg), it is intriguing to note that the time of appearance of the vacuolizations (4-12 h; Olney et al, 1999) closely corresponds to the times at which elevations in brain reward threshold were observed after the acute PCP doses. Interestingly, the same authors and others reported that chronic PCP treatment over 3-14 days causes irreversible necrotic toxicity and apoptosis that spreads to many corticolimbic brain regions (eg the amygdala, dentate gyrus, entorhinal cortex, olfactory tubercle, and piriform cortex; Ellison and Switzer, 1993;Ellison, 1994;Corso et al, 1997;Johnson et al, 1998;Phillips et al, 2001;Sharp et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

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Withdrawal from Chronic Phencyclidine Treatment Induces Long-Lasting Depression in Brain Reward Function

Spielewoy

Markou

2002

Neuropsychopharmacol

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Phencyclidine (PCP) is a drug of abuse that has rewarding and dysphoric effects in humans. The complex actions of PCP, and PCP withdrawal in particular, on brain reward function remain unclear. The purpose of the present study was to characterize the effects of withdrawal from acute and chronic PCP treatment on brain reward function in rats. A brain stimulation reward procedure was used to evaluate the effects of acute PCP injection (0, 5, or 10 mg/kg) or chronic PCP treatment (0, 10, 15, or 20 mg/kg/day for 14 days delivered via subcutaneous osmotic minipumps) on brain reward function. Withdrawal from acute administration of 5 and 10 mg/kg PCP produced a decrease in brain reward function as indicated by a sustained elevation in brain reward thresholds. When administered chronically, 10, 15, or 20 mg/kg/day PCP induced a progressive dose-dependent potentiation of brain stimulation reward, while cessation of the treatment resulted in significant elevations in reward thresholds reflecting diminished reward. Specifically, withdrawal from 15 or 20 mg/ kg/day PCP induced a depression in brain reward function that lasted for the entire month of observation. These results indicate that prolonged continuous administration of high PCP doses facilitates brain stimulation reward, while withdrawal from acute high PCP doses or chronic PCP treatment results in a protracted depression of brain reward function that may be analogous to the dysphoric and anhedonic symptoms observed in PCP dependence, depression, and schizophrenia.

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“…PCP and its structural analogue ketamine produce inactivation of inhibitory control by decreasing GABA release [58]. This disinhibition of excitatory neurotransmission is referred to as NMDA receptor hypofunction [32,45,46]. Acute administration of PCP in rats has been shown to produce deficits in the novel object recognition-NOR-task [21], an operant reversal learning paradigm [1,28] and attentional set-shifting [16].…”

Section: Introductionmentioning

confidence: 99%

A preliminary investigation into the effects of antipsychotics on sub-chronic phencyclidine-induced deficits in attentional set-shifting in female rats

McLean

Beck

Woolley

et al. 2008

Behavioural Brain Research

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Rationale: The NMDA receptor antagonist, phencyclidine (PCP), has been shown to induce symptoms characteristic of schizophrenia. A loss in executive function and the ability to shift attention between stimulus dimensions is impaired in schizophrenia; this can be assessed in rodents by the perceptual attentional set-shifting task. Objective: The aim of this study was to investigate whether the deficits induced by sub-chronic PCP in attentional set-shifting could be reversed by sub-chronic administration of clozapine, risperidone or haloperidol. Methods: Adult female hooded-Lister rats received subchronic PCP (2 mg/kg) or vehicle (1 ml/kg) i.p. twice daily for seven days, followed by a seven-day washout period. PCP-treated rats then received clozapine, risperidone, haloperidol or vehicle once daily for seven days and were then tested in the perceptual set-shifting task. Results: PCP significantly (p<0.01) increased the number of trials to reach criterion in the EDS phase when compared to vehicle and this deficit was significantly (p<0.01) attenuated by sub-chronic clozapine (2.5 mg/kg) and risperidone (0.2 mg/kg), but not by sub-chronic haloperidol treatment (0.05 mg/kg). Conclusions:These data show that sub-chronic PCP produced a robust deficit within the EDS phase in the attentional set-shifting task, in female rats. Atypical antipsychotics, clozapine and risperidone, but not the classical agent, haloperidol, significantly improved the PCPinduced cognitive deficit.

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NMDA receptor hypofunction model of schizophrenia

Cited by 928 publications

References 50 publications

Changes in NMDA receptor subunits and interacting PSD proteins in dorsolateral prefrontal and anterior cingulate cortex indicate abnormal regional expression in schizophrenia

Changes in NMDA receptor subunits and interacting PSD proteins in dorsolateral prefrontal and anterior cingulate cortex indicate abnormal regional expression in schizophrenia

Withdrawal from Chronic Phencyclidine Treatment Induces Long-Lasting Depression in Brain Reward Function

A preliminary investigation into the effects of antipsychotics on sub-chronic phencyclidine-induced deficits in attentional set-shifting in female rats

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