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Neuropsychopharmacology. 2014 Nov;39(12):2742-9. doi: 10.1038/npp.2014.4. Epub 2014 Feb 3.

Relationship between glycine transporter 1 inhibition as measured with positron emission tomography and changes in cognitive performances in nonhuman primates.

Author information

  • 1Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
  • 2Neurosciences Centre for Excellence in Drug Discovery, GlaxoSmithKline, Harlow, UK.
  • 3Clinical Imaging Centre, GlaxoSmithKline, Hammersmith Hospital-Imperial College, London, UK.
  • 4Department of Radiology, Yale University School of Medicine, New Haven, CT, USA.
  • 51] Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA [2] Neurosciences Centre for Excellence in Drug Discovery, GlaxoSmithKline, Harlow, UK [3] Department of Radiology, Yale University School of Medicine, New Haven, CT, USA [4] UCB Pharma, Braine-l'Alleud, Brussels, Belgium.

Abstract

Several lines of evidence suggest that schizophrenia is associated with deficits in glutamatergic transmission at the N-methyl-d-aspartate (NMDA) receptors. Glycine is a NMDA receptor co-agonist, and extracellular levels of glycine are regulated in the forebrain by the glycine type-1 transporters (GlyT-1). GlyT-1 inhibitors elevate extracellular glycine and thus potentiate NMDA transmission. This mechanism represents a promising new avenue for the treatment of schizophrenia. Here, the recently introduced positron emission tomography radiotracer [11C]GSK931145 was used to quantify the relationship between occupancy of GlyT-1 by a GlyT-1 inhibitor, Org 25935, and its impact on spatial working memory performances in rhesus monkeys. The effect of Org 25935 on working memory was assessed both in control conditions and during a state of relative NMDA hypofunction induced by ketamine administration, at a dose selected for each animal to reduce task performance by about 50%. Under control conditions, Org 25935 had no effect on working memory at GlyT-1 occupancies lower than 75% and significantly impaired working memory at occupancies higher than 75%. Under ketamine conditions, Org 25935 reversed the deficit in working memory induced by ketamine and did so optimally in the 40-70% GlyT-1 occupancy range. The results confirm the efficacy of this mechanism to correct working memory deficits associated with NMDA hypofunction. These data also suggest the existence of an inverted-U dose-response curve in the potential therapeutic effect of this class of compounds.

PMID:
24487737
[PubMed - in process]
PMCID:
PMC4200505
[Available on 2015-11-01]
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