Modulators of the glycine site on NMDA receptors, d-serine and ALX 5407, display similar beneficial effects to clozapine in mouse models of schizophrenia

@article{Lipina2005ModulatorsOT,
  title={Modulators of the glycine site on NMDA receptors, d-serine and ALX 5407, display similar beneficial effects to clozapine in mouse models of schizophrenia},
  author={Tatiana V. Lipina and Viviane Labrie and Ina Weiner and John C. Roder},
  journal={Psychopharmacology},
  year={2005},
  volume={179},
  pages={54-67}
}
RationaleSchizophrenia is characterized by disturbances in sensorimotor gating and attentional processes, which can be measured by prepulse inhibition (PPI) and latent inhibition (LI), respectively. Research has implicated dysfunction of neurotransmission at the NMDA-type glutamate receptor in this disorder.ObjectivesThis study was conducted to examine whether compounds that enhance NMDA receptor (NMDAR) activity via glycine B site, d-serine and ALX 5407 (glycine transporter type 1 inhibitor… 
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Glycine and d-serine, but not d-cycloserine, attenuate prepulse inhibition deficits induced by NMDA receptor antagonist MK-801
TLDR
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TLDR
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RationaleGlutamatergic abnormalities are involved in the etiology of schizophrenia. Clinical evidence demonstrates that positive modulation of “glycine modulatory sites” on N-methyl-d-aspartic acid
Procognitive and antipsychotic efficacy of glycine transport 1 inhibitors (GlyT1) in acute and neurodevelopmental models of schizophrenia: latent inhibition studies in the rat
TLDR
Preclinical data, from acute and neurodevelopmental models, suggest that GlyT1 inhibition may exhibit activity in the positive, negative, and cognitive symptom domains of schizophrenia.
The Glycine Transporter-1 Inhibitor SSR103800 Displays a Selective and Specific Antipsychotic-like Profile in Normal and Transgenic Mice
TLDR
Findings show that the GlyT1 inhibitor, SSR103800, produces antipsychotic-like effects, which differ from those observed with compounds primarily targeting the dopaminergic system, and has a reduced side-effect potential as compared with these latter drugs.
Abnormally persistent latent inhibition induced by MK801 is reversed by risperidone and by positive modulators of NMDA receptor function: differential efficacy depending on the stage of the task at which they are administered
TLDR
These results support the validity of MK801-induced persistent LI as a model of negative/cognitive symptoms in SZ and indicate that this model may have a unique capacity to discriminate between typical APD, atypical APDs, and glycinergic compounds, and thus, foster the identification of novel treatments for SZ.
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References

SHOWING 1-10 OF 80 REFERENCES
Glycine and D-serine decrease MK-801-induced hyperactivity in mice
TLDR
Investigating if it is possible to strengthen NMDA receptor-mediated neurotransmission by modulating the associated glycine site found it to be possible, and the effects of systemic and intraventricular administration of glycine, D-Serine and L-serine on the hyperactivity induced in mice by the uncompetitiveNMDA receptor antagonist MK-801 were tested.
N-methyl-D-aspartate receptor-coupled glycineB receptors in the pathogenesis and treatment of schizophrenia: a critical review.
  • M. Millan
  • Psychology, Medicine
    Current drug targets. CNS and neurological disorders
  • 2002
TLDR
The complex role of GLY(B) sites/NMDA receptors and their endogenous ligands in the pathogenesis and treatment of psychotic states is reviewed and blockade of certain populations of NMDA receptor may be of use in the management of schizophrenia.
Systemic administration of MK-801 produces an abnormally persistent latent inhibition which is reversed by clozapine but not haloperidol
TLDR
MK-801-induced perseveration of LI is consistent with other reports of perseverative behaviors, suggested to be particularly relevant to negative symptoms of schizophrenia, following NMDA receptor blockade, and the model may provide a unique screening tool for the identification of novel antipsychotic compounds.
Reversal of phencyclidine-induced effects by glycine and glycine transport inhibitors
Clozapine modulates midbrain dopamine neuron firing via interaction with the NMDA receptor complex
TLDR
The inhibitory action of clozapine on VTA DA neurons may account for its beneficial effects in ameliorating symptoms of schizophrenia and may suggest further studies to investigate a role of the glycine site of the NMDA receptor as a target for novel antipsychotics.
Glycine modulators in schizophrenia.
  • D. Javitt
  • Psychology, Medicine
    Current opinion in investigational drugs
  • 2002
TLDR
Recently developed glycine transport inhibitors (GTI) have preclinical behavioral effects similar to those of glycine or D-serine, and may represent a 'next generation' approach to the treatment of the persistent negative and cognitive symptoms of schizophrenia.
The 5-HT2A receptor antagonist M100,907 attenuates motor and 'impulsive-type' behaviours produced by NMDA receptor antagonism
TLDR
The results suggest that 5-HT2A receptor antagonists may normalise certain 'impulsive' behaviours produced by NMDA receptor hypofunction, as well as attenuate the hyperlocomotion and stereotypy produced by dizocilpine.
The Glycine Transporter Type 1 Inhibitor N-[3-(4′-Fluorophenyl)-3-(4′-Phenylphenoxy)Propyl]Sarcosine Potentiates NMDA Receptor-Mediated Responses In Vivo and Produces an Antipsychotic Profile in Rodent Behavior
TLDR
The present study found that (+)-NFPS demonstrated >10-fold greater activity in an in vitro functional glycine reuptake assay relative to the racemic compound, suggesting that selective inhibition of GlyT1 can enhance NMDAR-sensitive activity in vivo and also support the idea that GlyT 1 may represent a novel target for developing therapeutics to treat disorders associated with NMDar hypofunction.
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