Abstract
N-methyl-D-aspartate receptors (NMDARs) represent a subclass of glutamate receptors that play a critical role in neuronal development and physiology. We report here the generation of mice expressing only 5% of normal levels of the essential NMDAR1 (NR1) subunit. Unlike NR1 null mice, these mice survive to adulthood and display behavioral abnormalities, including increased motor activity and stereotypy and deficits in social and sexual interactions. These behavioral alterations are similar to those observed in pharmacologically induced animal models of schizophrenia and can be ameliorated by treatment with haloperidol or clozapine, antipsychotic drugs that antagonize dopaminergic and serotonergic receptors. These findings support a model in which reduced NMDA receptor activity results in schizophrenic-like behavior and reveals how pharmacological manipulation of monoaminergic pathways can affect this phenotype.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antipsychotic Agents / therapeutic use
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Antisocial Personality Disorder / drug therapy
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Antisocial Personality Disorder / genetics
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Behavior, Animal* / drug effects
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Calcium Signaling / drug effects
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Clozapine / pharmacology
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Clozapine / therapeutic use
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Disease Models, Animal*
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Dizocilpine Maleate / toxicity
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Dopamine Antagonists / pharmacology
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Dopamine Antagonists / therapeutic use
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Excitatory Amino Acid Antagonists / toxicity
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Female
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Glutamic Acid / physiology
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Haloperidol / pharmacology
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Haloperidol / therapeutic use
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Male
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Mice
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Mice, Knockout
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Motor Activity / drug effects
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Motor Activity / genetics
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Phencyclidine / toxicity
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Receptors, N-Methyl-D-Aspartate / deficiency*
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Receptors, N-Methyl-D-Aspartate / genetics
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Receptors, N-Methyl-D-Aspartate / physiology
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Schizophrenic Psychology*
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Serotonin Antagonists / pharmacology
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Serotonin Antagonists / therapeutic use
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Sexual Behavior, Animal / drug effects
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Social Behavior
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Stereotyped Behavior / drug effects
Substances
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Antipsychotic Agents
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Dopamine Antagonists
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Excitatory Amino Acid Antagonists
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NMDA receptor A1
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Receptors, N-Methyl-D-Aspartate
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Serotonin Antagonists
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Glutamic Acid
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Dizocilpine Maleate
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Phencyclidine
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Clozapine
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Haloperidol