A Pharmacological Model for Psychosis Based on N-methyl-D-aspartate Receptor Hypofunction: Molecular, Cellular, Functional and Behavioral Abnormalities

doi:10.1016/j.biopsych.2005.08.029

Biological Psychiatry

Volume 59, Issue 8, 15 April 2006, Pages 721-729

https://doi.org/10.1016/j.biopsych.2005.08.029 Get rights and content

Background

The psychotomimetic effects of N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP) in healthy humans and their ability to exacerbate psychotic symptoms in schizophrenic patients have promoted a view of schizophrenia as being related to altered glutamatergic neurotransmission.

Methods

This prompted us and others to develop animal models for psychosis based on a glutamatergic approach. Pharmacological induction of a state of impaired glutamatergic neurotransmission based on chronic, low-dose application of MK-801, a highly selective noncompetitive NMDA antagonist, revealed marked parallels between schizophrenia and our animal model.

Results

MK-801 altered the expression of NR1 splice variants and NR2 subunits of the NMDA receptor in a pattern partially resembling the alterations detected in schizophrenia. Ultrastructurally, the number of gamma-aminobutyric-acid (GABA)ergic parvalbumin-positive interneurons was relatively decreased, a finding which again parallels observations in post mortem brain from schizophrenic patients. As a functional consequence, local inhibition of pyramidal cells which is largely mediated by recurrent axon collaterals, originating from GABAergic interneurons, was altered. Not unexpectedly, these animals showed cognitive deficits resembling findings in schizophrenic humans.

Conclusions

These convergent lines of evidence suggest that our approach has a significant potential of serving as a model of the pathobiology of several aspects of psychosis and consequently could contribute to the development of new therapeutic strategies.

Section snippets

Animals

Juvenile male Long Evans rats (n = 22; age 32–40 days; weight 124–152 g) were matched according to body weight and housed in groups of two in cages in a temperature controlled room (23°C), with a 12/12 hour light/dark cycle, and with food and water provided ad libitum. They received daily intraperitoneal injections (10 ml/kg body weight, .9% saline as vehicle) of either .02 mg/kg body weight (+)-MK-801 maleate (n = 11) [(5R,10S)-(+)-5-methyl-10,11-dihydro-5I-dibenzo[a,b]cyclohepten-5,10-imine

Differential Expression of NMDA Receptor mRNA Subunits and Splice Variants

Chronic mild treatment with MK-801 shifted the ratio of NR1 exon 5 inclusion/exclusion towards exon 5 inclusion splice variant in the hippocampus (1.23 ± .09 vs. 1.07 ± .09 in controls, t = 2.697, df = 8, p = .027) (Table 2).

The hippocampal ratio of NR2C to NR2A expression was decreased in the MK-801 group (.67 ± .11 vs. .54 ± .03 in controls, t = 2.691, df = 8, p = .027) (Table 2).

Chronic mild MK-801 treatment decreased the mRNA expression of the NR2B subunit relative to GAPDH in the

References (64)

K.M. Abel et al.
Low dose ketamine increases prepulse inhibition in healthy men
Neuropharmacology
(2003)
D.G. Amaral et al.
The three-dimensional organization of the hippocampal formationa review of anatomical data
Neuroscience
(1989)
C.L. Beasley et al.
Parvalbumin-immunoreactive neurons are reduced in the prefrontal cortex of schizophrenics
Schizophr Res
(1997)
F.M. Benes et al.
GABAergic interneuronsimplications for understanding schizophrenia and bipolar disorder
Neuropsychopharmacology
(2001)
F.M. Benes et al.
A reduction of nonpyramidal cells in sector CA2 of schizophrenics and manic depressives
Biol Psychiatry
(1998)
G. Buzsaki et al.
Temporal structure in spatially organized neuronal ensemblesa role for interneuronal networks
Curr Opin Neurobiol
(1995)
Q. Chen et al.
Cellular expression of ionotropic glutamate receptor subunits on specific striatal neuron types and its implication for striatal vulnerability in glutamate receptor-mediated excitotoxicity
Neuroscience
(1996)
M.R. del Rio et al.
Colocalization of parvalbumin and calbindin D-28k in neurons including chandelier cells of the human temporal neocortex
J Chem Neuroanat
(1997)
R. Dingledine et al.
Conductance changes and inhibitory actions of hippocampal recurrent IPSPs
Brain Res
(1980)
M.F. Egan et al.
Neurobiology of schizophrenia
Curr Opin Neurobiol
(1997)

M. Frotscher et al.

Commissural fibers terminate on nonpyramidal neurons in the guinea pig hippocampus–a combined Golgi/EM degeneration study

Brain Res

(1983)

G. Keilhoff et al.

Repeated application of ketamine to rats induces changes in the hippocampal expression of parvalbumin, neuronal nitric oxide synthase and cFOS similar to those found in human schizophrenia

Neuroscience

(2004)

A.C. Lahti et al.

Subanesthetic doses of ketamine stimulate psychosis in schizophrenia

Neuropsychopharmacology

(1995)

A.C. Lahti et al.

Effects of ketamine in normal and schizophrenic volunteers

Neuropsychopharmacology

(2001)

W. Lukas et al.

Cortical neurons containing calretinin are selectively resistant to calcium overload and excitotoxicity in vitro

Neuroscience

(1994)

R.W. McCarley et al.

MRI anatomy of schizophrenia

Biol Psychiatry

(1999)

A.R. Mohn et al.

Mice with reduced NMDA receptor expression display behaviors related to schizophrenia

Cell

(1999)

B.J. Morris et al.

PCPfrom pharmacology to modeling schizophrenia

Curr Opin Pharmacol

(2005)

L.T. Niemi et al.

Childhood developmental abnormalities in schizophreniaevidence from high-risk studies

Schizophr Res

(2003)

G. Paxinos et al.

AChE-stained horizontal sections of the rat brain in stereotaxic coordinates

J Neurosci Methods

(1980)

R. Ritz et al.

Synchronous oscillatory activity in sensory systemsnew vistas on mechanisms

Curr Opin Neurobiol

(1997)

J.M. Rodriguez-Paz et al.

Block of the N-methyl-D-aspartate receptor by phencyclidine-like drugs is influenced by alternative splicing

Neurosci Lett

(1995)

A.F. Sadikot et al.

NMDA receptor antagonists influence early development of GABAergic interneurons in the mammalian striatum

Brain Res Dev Brain Res

(1998)

T. Schiffelholz et al.

Perinatal MK-801 treatment affects age-related changes in locomotor activity from childhood to later adulthood in rats

Neurosci Lett

(2004)

E.F. Torrey et al.

Neurochemical markers for schizophrenia, bipolar disorder, and major depression in postmortem brains

Biol Psych

(2005)

H.J. Waldvogel et al.

Differential sensitivity of calbindin and parvalbumin immunoreactive cells in the striatum to excitotoxins

Brain Res

(1991)

Z.J. Zhang et al.

A selective decrease in the relative density of parvalbumin-immunoreactive neurons in the hippocampus in schizophrenia

Schizophr Res

(2002)

R.S. Zukin et al.

Alternatively spliced isoforms of the NMDARI receptor subunit

Trends Neurosci

(1995)

Y. Aika et al.

Quantitative analysis of GABA-like-immunoreactive and parvalbumin-containing neurons in the CA1 region of the rat hippocampus using a stereological method, the disector

Exp Brain Res

(1994)

P. Andersen et al.

Recurrent inhibition in the hippocampus with identification of the inhibitory cell and its synapses

Nature

(1963)

S.E. Arnold

The medial temporal lobe in schizophrenia

J Neuropsychiatry Clin Neurosci

(1997)

A. Bertolino et al.

Specific relationship between prefrontal neuronal N-acetylaspartate and activation of the working memory cortical network in schizophrenia

Am J Psychiatry

(2000)

Cited by (201)

Chronic MK-801 administration provokes persistent deficits in social memory in the prairie vole (Microtus ochrogaster): A potential animal model for social deficits of schizophrenia
2024, Behavioural Brain Research
The prairie vole (Microtus ochrogaster) is a rodent species that has been used extensively to study biological aspects of human social bonding. Nevertheless, this species has not been studied in the context of modeling social deficits characteristic of schizophrenia. Building on studies in rodents that show that sub-chronic administration of an NMDA receptor antagonist induces persistent behavioral and neurological characteristics of schizophrenia, we administered MK-801 (0.2 mg/kg, daily, for 7 days) or physiological saline to young adult (45 days old) virgin male voles. At 69 days of age, we paired these males with virgin females. 24 h later, we assessed the males’ social investigation of each female across the first 5 min of a three-hour preference test, and side-by-side contact with each female during the last hour of the test. Unlike saline-treated males, MK-801-treated males did not preferentially investigate the unfamiliar female, indicating a deficit in social memory. Although males of both groups preferentially spent time with their female partner, regression analysis revealed that deficits in social memory predicted lower partner preference in MK-801-treated males. We interpret these results in the context of recent studies of the natural history of the prairie vole as well as in the context of cognitive deficits in schizophrenia and propose that the social component of episodic memory might influence an individual’s capacity to form and maintain long-term social bonds.
Low-dose lithium mono- and adjunctive therapies improve MK-801-induced cognitive impairment and schizophrenia-like behavior in mice - Evidence from altered prefrontal lobe Ca<sup>2+</sup> activity
2023, Journal of Affective Disorders
Few studies have evaluated lithium either as monotherapy or in combination with anti-psychotic agents to improve cognition in murine models of schizophrenia.
Visualization of Ca²⁺ activity in the prefrontal cortex was used to characterize brain neural activity. Novel object recognition (NOR), Morris water maze (MWM), and fear conditioning (FCT) tests were used to characterize cognitive performance; while pre-pulse inhibition (PPI), elevated plus maze (EPM) and the open field test (OFT) were used to characterize schizophrenia-like behavior.
A 28-day course of low-dose lithium (human equivalent dose of 250 mg/day) combined with moderate-dose quetiapine (human equivalent dose of 600 mg/day) improved Ca²⁺ ratio by 70.10 %, PPI by 69.28 %, NOR by 70.09 %, MWM by 71.28 %, FCT by 68.56 %, EPM by 70.95 % and OFT by 75.23 % compared to the results of positive controls. Unexpectedly, moderate-dose lithium (human equivalent dose of 500 mg/day) used either as monotherapy or as an adjunct with quetiapine worsened Ca²⁺ activity, PPI, MWM, FCT, EPM, and OPT.
Our study cannot explain the contrasting positive and negative effects of low-dose and moderate-dose lithium, respectively, when used either as monotherapies or as adjuncts. Further studies, especially Western blotting, may reveal molecular mechanisms of action.
Low-dose lithium (human equivalent dose of 250 mg/day) combined with moderate-dose quetiapine (human equivalent dose of 600 mg/day) provided the best improvements. Furthermore, benefits persisted for 14 days post-treatment. Our data provide directions for further research of therapeutic alternatives to mitigate schizophrenia-related cognopathy.
Glutamate metabolites in treatment resistant schizophrenia: A meta-analysis and systematic review of <sup>1</sup>H-MRS studies
2020, Psychiatry Research - Neuroimaging
Nearly a third to half of schizophrenia patients are non-responsive to first-line antipsychotics and are labelled treatment resistant schizophrenia (TRS). Neurochemical abnormalities in TRS may not be dopaminergic but possibly glutamate (Glu) related. Studies that have examined glutamatergic abnormalities using proton magnetic resonance spectroscopy (¹H-MRS) in TRS, have showed inconsistent results. Hence, we conducted a meta-analysis of ¹H-MRS studies comparing levels of Glu-and its metabolites in the brains of TRS and non-treatment resistant schizophrenia (nTRS) patients. Four eligible studies were included in the analysis. Summary effect size for the group difference between TRS (n = 101, including Ultra-TRS) and nTRS (n = 61) in Glu-levels in the anterior cingulate cortex (ACC) as measured with Hedges's g was 0.21 (95% CI: -0.42 to 0.85; p = 0.5) suggesting absence of significant difference. However, on leave one out analysis, one iteration showed significant difference in Glu-levels between the groups (Hedges's g = 0.46; p = 0.02) with higher Glu-levels in TRS implying significant effect of a single study on the effect size. The higher ACC Glu-in TRS was not associated with symptom severity or antipsychotic administration, indicating a possible trait abnormality. The limited number of datasets comparing Glu-metabolites in other brain regions are narratively described. Our analysis is limited by the significant heterogeneity between studies. Further longitudinal, prospective studies are needed to confirm higher Glu-metabolite levels in ACC in TRS and explore this potential trait abnormality.
Subchronic MK-801 treatment during adolescence induces long-term, not permanent, excitatory-inhibitory imbalance in the rat hippocampus
2020, European Journal of Pharmacology
Adolescence is a critical neurodevelopmental period for both excitatory and inhibitory (E/I) neurotransmission and often witnesses the typical onsets of schizophrenia. One possibility is that disruptions in adolescent neurodevelopmental processes may produce schizophrenia-like behavioral and neurobiological abnormalities. We previously reported that subchronic treatment of adolescent animals with the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 induced cognitive deficits and reduced interneuron densities in rat medial prefrontal cortex, and these changes persisted one week after MK-801 exposure. However, it remains unclear how this treatment may affect E/I balance in hippocampus, which has long been associated with the pathophysiology of schizophrenia. Here, we examined hippocampal E/I biomarkers in adolescent rats treated with MK-801 (0.2 mg/kg, i.p., 14 days) and found increases in the ratio of the expression levels of vesicular glutamate transporter-1 (VGluT1) and vesicular gamma-aminobutyric acid (GABA) transporter (VGAT) 24 h and 7 days after MK-801 exposure. Interestingly, the increased VGluT1/VGAT ratio at the two time points was driven by upregulated VGluT1 expression and downregulated VGAT expression, respectively. The decrease in VGAT expression persisted 14 days after MK-801 exposure and recovered two weeks later. No alterations in hippocampal interneuron densities were observed. Behaviorally, the treatment decreased prepulse inhibition at 24 h but not 14 days, after MK-801 exposure. Taken together, these results demonstrate that subchronic NMDA receptor blockade during adolescence induces long-term, but not permanent, E/I imbalance in the rat hippocampus, which could be attributed to the dysregulation of glutamatergic transmission in the short term and of GABAergic transmission in the long term.
Age-dependent effects of (+)-MK801 treatment on glutamate release and metabolism in the rat medial prefrontal cortex
2019, Neurochemistry International
NMDAR antagonist treatments in adolescent/young adult rodents are associated with augmented glutamate (Glu) release and perturbed Glu/glutamine (Gln) metabolism in the medial prefrontal cortex (mPFC) resembling those found in first-episode schizophrenia. Few studies, however, investigated NMDAR antagonist-induced changes in the adult mPFC and whether there is an age-dependence to this end. In this study, the effects of acute/repeated (+)-MK801 treatment on Glu release/metabolism were measured in the mPFC of male adolescent (postnatal day 30) and adult (14 weeks) rats. Acute (+)-MK801 treatment at 0.5 mg/kg body weight induced an approximately 4-fold increase of extracellular Glu concentration in the adolescent rats, and repeated treatment for 6 consecutive days significantly increased the levels of Glu + Gln (Glx) and glial metabolites 7 days after the last dose. Histologically (+)-MK801 treatments induced reactive astrocytosis and elevated oxidative stress in the mPFC of adolescent rats, without causing evident neuronal degeneration in the region. All (+)-MK801-induced changes observed in the mPFC of adolescent rats were not present or evident in the adult rats, suggesting that the treatments might have caused less disinhibition in the adult mPFC than in the adolescent mPFC. In conclusion, the effects of (+)-MK801 treatments on the Glu release/metabolism in the mPFC were found to be age-dependent; and the adult mPFC is likely equipped with more robust neurobiological mechanisms to preserve excitatory-inhibitory balance in response to NMDAR hypofunction.
Atypical but not typical antipsychotic drugs ameliorate phencyclidine-induced emotional memory impairments in mice
2019, European Neuropsychopharmacology
Schizophrenia is associated with cognitive impairments related to hypofunction in glutamatergic N-methyl-D-aspartate receptor (NMDAR) transmission. Phencyclidine (PCP), a non-competitive NMDAR antagonist, models schizophrenia-like behavioral symptoms including cognitive deficits in rodents. This study examined the effects of PCP on emotional memory function examined in the passive avoidance (PA) task in mice and the ability of typical and atypical antipsychotic drugs (APDs) to rectify the PCP-mediated impairment. Pre-training administration of PCP (0.5, 1, 2 or 3 mg/kg) dose-dependently interfered with memory consolidation in the PA task. In contrast, PCP was ineffective when administered after training, and immediately before the retention test indicating that NMDAR blockade interferes with memory encoding mechanisms. The typical APD haloperidol and the dopamine D_2/3 receptor antagonist raclopride failed to block the PCP-induced PA impairment suggesting a negligible role of D₂ receptors in the PCP impairment. In contrast, the memory impairment was blocked by the atypical APDs clozapine and olanzapine in a dose-dependent manner while risperidone was effective only at the highest dose tested (1 mg/kg). The PCP-induced impairment involves 5-HT_1A receptor mechanisms since the antagonist NAD-299 blocked the memory impairment caused by PCP and the ability of clozapine to attenuate the impairment by PCP. These results indicate that atypical but not typical APDs can ameliorate NMDAR-mediated memory impairments and support the view that atypical APDs such as clozapine can modulate glutamatergic memory dysfunctions through 5-HT_1A receptor mechanisms. These findings suggest that atypical APDs may improve cognitive impairments related to glutamatergic dysfunction relevant for emotional memories in schizophrenia.

View all citing articles on Scopus

View full text

Original articleA Pharmacological Model for Psychosis Based on N-methyl-D-aspartate Receptor Hypofunction: Molecular, Cellular, Functional and Behavioral Abnormalities

Background

Methods

Results

Conclusions

Section snippets

Animals

Differential Expression of NMDA Receptor mRNA Subunits and Splice Variants

Neuropharmacology

Neuroscience

Schizophr Res

Neuropsychopharmacology

Biol Psychiatry

Curr Opin Neurobiol

Neuroscience

J Chem Neuroanat

Brain Res

Curr Opin Neurobiol

Brain Res

Neuroscience

Neuropsychopharmacology

Neuropsychopharmacology

Neuroscience

Biol Psychiatry

Cell

Curr Opin Pharmacol

Schizophr Res

J Neurosci Methods

Curr Opin Neurobiol

Neurosci Lett

Brain Res Dev Brain Res

Neurosci Lett

Biol Psych

Brain Res

Schizophr Res

Trends Neurosci

Quantitative analysis of GABA-like-immunoreactive and parvalbumin-containing neurons in the CA1 region of the rat hippocampus using a stereological method, the disector

Exp Brain Res

Recurrent inhibition in the hippocampus with identification of the inhibitory cell and its synapses

Nature

The medial temporal lobe in schizophrenia

J Neuropsychiatry Clin Neurosci

Specific relationship between prefrontal neuronal N-acetylaspartate and activation of the working memory cortical network in schizophrenia

Am J Psychiatry

Original article
A Pharmacological Model for Psychosis Based on N-methyl-D-aspartate Receptor Hypofunction: Molecular, Cellular, Functional and Behavioral Abnormalities