title: GlyT1 inhibitor reduces oscillatory potentials of the electroretinogram in rats.
abstract: BACKGROUND
  Selective inhibitors of glycine transporter type 1 (GlyT1) increase synaptic glycine concentrations and are being developed to treat cognitive and negative symptoms of schizophrenia. However, increases in systemic glycine levels have been associated with visual disturbances and electroretinogram (ERG) alternations.
  
  
  OBJECTIVE
  To determine whether the selective GlyT1 inhibitor PF-03463275 causes changes in ERG responses in albino rats.
  
  
  METHODS
  Male Sprague-Dawley rats were administered PF-03463275 subcutaneously at 1, 3 and 10 mg/kg 1 h prior to ERG acquisition. Scotopic and photopic luminance responses, photopic adaptometry and flicker responses were measured. Plasma and vitreous samples were obtained at necropsy for determination of PF-03463275 concentrations.
  
  
  RESULTS
  A dose-dependent reduction (up to ∼70%) in the amplitude of the scotopic ERG oscillatory potentials (OPs) was observed following PF-03463275 administration. The amplitude of the OPs was also negatively correlated to the concentration of PF-03463275 in the vitreous humor (r = -0.64, p < 0.0001). With the exception of a small increase in scotopic ERG a-wave amplitude and latency no effects were observed on other ERG parameters tested.
  
  
  CONCLUSIONS
  We conclude that inhibition of the GlyT1 transporter in the retina causes ERG changes which may underlie recent reports of visual disturbance with GlyT1 inhibitors in clinical trials.
authors.affiliation: Drug Safety R&D and.
authors.forename: Chang-Ning
authors.initials: CN
authors.lastname: Liu
authors.forename: Betty
authors.initials: B
authors.lastname: Pettersen
authors.forename: Gary
authors.initials: G
authors.lastname: Seitis
authors.forename: Sarah
authors.initials: S
authors.lastname: Osgood
authors.forename: Chris
authors.initials: C
authors.lastname: Somps
mesh_terms: D000818:Animals; D053961:Azabicyclo Compounds / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D004596:Electroretinography / Q000187:drug effects; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D007093:Imidazoles / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D010775:Photic Stimulation; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000187:drug effects* / Q000502:physiology; D014822:Vitreous Body / Q000378:metabolism
chemical_list: C549926:1-methyl-1H-imidazole-4-carboxylic acid (3-chloro-4-fluoro-benzyl)-(3-methyl-3-aza-bicyclo(3.1.0) hex-6-ylmethyl)amide; D053961:Azabicyclo Compounds; D050487:Glycine Plasma Membrane Transport Proteins; D007093:Imidazoles; C493266:Slc6a9 protein, rat
keywords: Drug development; Sprague-Dawley rat; electroretinography; flash ERG; retina; schizophrenia