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Inhibition of Glycine Transporter-1 Improves the Functional Outcome of Schizophrenia

  • Christina Hui
  • Guochuan E. TsaiEmail author
Chapter

Abstract

Although current antipsychotic medications are able to reduce psychotic symptoms by blocking dopamine 2 (D2) receptors, they are limited in their ability to treat certain aspects of schizophrenia, such as flat affect, social withdrawal, and cognitive impairments, all which influence an individual’s ability to function in society. For over fifteen years, increasing emphasis has been placed on hypofunction at the N-methyl-D-aspartate receptor (NMDAR) as a potential mechanism underlying the pathophysiology of schizophrenia. Altering NMDAR-mediated neurotransmission by targeting components of the glutamatergic synapse offers a new paradigm by which to generate new drugs to treat schizophrenia. The potential for improving cognitive symptoms, with the ultimate goal of improving functional outcome, is especially alluring given NMDAR’s critical role in learning and memory. Several clinical trials have been conducted with agents that enhance NMDAR function by increasing activity at the glycine co-agonist site (GCS). The GCS can be directly activated by amino acids, such as glycine or D-serine, or indirectly, by blocking glycine transporter-1 (GlyT-1) reuptake of glycine from the synaptic cleft. While there have been limited clinical trials of GlyT-1 inhibitors in humans, translational research in animal models has demonstrated the antipsychotic effects and cognitive enhancement of these agents. Thus, the 21st century holds promise as the era in which an entirely new type of medication for schizophrenia may be created, one with more success at treating the debilitating negative and cognitive symptoms of this disease.

Keywords

NMDA receptors GlyT-1 inhibitors Sarcosine D-serine Glycine Glycine co-agonist site 

Abbreviations

AMPA

alpha-amino-3-hydroxy-5-methyl-4-isozadole-4-proprionate

BDNF

brain derived neurotrophic factor

CATIE

Clinical antipsychotic trials of intervention effectiveness

CREB

cAMP response element binding protein

DAAO

D-amino acid oxidase

DAT

dopamine transporters

EPS

extrapyramidal symptoms

GABA

gamma-aminobutyric acid

EAAT

glutamate transporters

GCS

glycine co-agonist site

GlyT-1

glycine transporter-1

LTD

long term depression

LTP

long term ptoentiation

MATRICS

Measurement and Treatment Research to Improve Cognition in Schizophrenia

MK-801

diclozipine

NFPS

N[3-(4-flurophenyl)-3-(4phenyl-phenylphenoxy)propyl]sarcosine

NMDA

N-methyl-D-aspartate

PANSS

Positive and Negative Syndrome Scale

PCP

phencyclidine

PET

positron emission tomography

PICK1

protein interacting C-kinase-1

PSD

postsynaptic density

PPI

prepulse inhibition

RCT

randomized control trials

SR

serine racemase

SNPs

single nucleotide polymorphisms

vGluT1

vesicular glutamate transporter-1

Notes

Acknowledgements

GET is supported in part by Los Angeles Biomedical Research Institute and National Alliance of Research on Schizophrenia and Affective Disorder.

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Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  1. 1.Department of PsychiatryHarbor–UCLA Medical CenterTorranceUSA
  2. 2.Department of PsychiatryHarbor–UCLA Medical CenterTorranceUSA

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