Abstract | RATIONALE: Schizophrenic patients demonstrate prominent negative and cognitive symptoms that are poorly responsive to antipsychotic treatment. Abnormal glutamatergic neurotransmission may contribute to these pathophysiological dimensions of schizophrenia. OBJECTIVE: MATERIALS AND METHODS: Behavioral phenotypes relevant to schizophrenia were assessed in Grin1(D481N) mice that have reduced NMDAR glycine affinity. RESULTS: Grin1(D481N) mutant mice showed abnormally persistent latent inhibition (LI) that was reversed by two agents that enhance NMDAR glycine site function, D: - serine (600 mg/kg) and ALX-5407 (1 mg/kg), and by the classical atypical antipsychotic clozapine (3 mg/kg). Similarly, blockade of the NMDAR glycine site with the antagonist L-701,324 (5 mg/kg) induced persistent LI in C57BL6/J mice. In a social affiliations task, Grin1(D481N) mutant animals showed reduced social approach behaviors that were normalized by D: - serine (600 mg/kg). During a nonassociative spatial object recognition task, mutant mice demonstrated impaired reactivity to a spatial change that was reversible by D: - serine (300 and 600 mg/kg) and clozapine (0.75 mg/kg). In contrast, responses to social novelty and nonspatial change remained unaffected, indicating that the Grin1(D481N) mutation induces selective deficits in sociability and spatial discrimination, while leaving intact the ability to react to novelty. CONCLUSIONS: Genetic and pharmacologically induced deficiencies in glycine binding appear to model the impairments in behavioral flexibility, sociability, and spatial recognition related to the negative and cognitive symptoms of schizophrenia. Antipsychotics that target the NMDAR glycine site may be beneficial in treating such psychiatric symptoms.
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Authors | Viviane Labrie, Tatiana Lipina, John C Roder |
Journal | Psychopharmacology
(Psychopharmacology (Berl))
Vol. 200
Issue 2
Pg. 217-30
(Oct 2008)
ISSN: 0033-3158 [Print] Germany |
PMID | 18597079
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- (R)-(N-(3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl))sarcosine
- Carrier Proteins
- Gprin1 protein, mouse
- Nerve Tissue Proteins
- Quinolones
- Receptors, N-Methyl-D-Aspartate
- Serine
- L 701324
- Clozapine
- Glycine
- Sarcosine
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Topics |
- Animals
- Behavior, Animal
- Carrier Proteins
(genetics)
- Clozapine
(pharmacology)
- Disease Models, Animal
- Glycine
(metabolism)
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Mutant Strains
- Nerve Tissue Proteins
(genetics)
- Phenotype
- Quinolones
(pharmacology)
- Receptors, N-Methyl-D-Aspartate
(drug effects, metabolism)
- Recognition, Psychology
(drug effects)
- Sarcosine
(analogs & derivatives, pharmacology)
- Schizophrenia
(physiopathology)
- Schizophrenic Psychology
- Serine
(administration & dosage, pharmacology)
- Social Behavior
- Space Perception
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