Relationship between glycine transporter 1 inhibition as measured with positron emission tomography and changes in cognitive performances in nonhuman primates.
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.
Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
S A
SA
Castner
Neurosciences Centre for Excellence in Drug Discovery, GlaxoSmithKline, Harlow, UK.
N V
NV
Murthy
Clinical Imaging Centre, GlaxoSmithKline, Hammersmith Hospital-Imperial College, London, UK.
K
K
Ridler
Neurosciences Centre for Excellence in Drug Discovery, GlaxoSmithKline, Harlow, UK.
H
H
Herdon
Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
B M
BM
Roberts
Department of Radiology, Yale University School of Medicine, New Haven, CT, USA.
D P
DP
Weinzimmer
Department of Radiology, Yale University School of Medicine, New Haven, CT, USA.
Y
Y
Huang
Department of Radiology, Yale University School of Medicine, New Haven, CT, USA.
M Q
MQ
Zheng
Clinical Imaging Centre, GlaxoSmithKline, Hammersmith Hospital-Imperial College, London, UK.
E A
EA
Rabiner
Clinical Imaging Centre, GlaxoSmithKline, Hammersmith Hospital-Imperial College, London, UK.
R N
RN
Gunn
Department of Radiology, Yale University School of Medicine, New Haven, CT, USA.
R E
RE
Carson
Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
G V
GV
Williams
1] 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.
M
M
Laruelle
D000818:Animals; D001549:Benzamides; D001921:Brain / Q000000981:diagnostic imaging / Q000502:physiology*; D002250:Carbon Radioisotopes; D002491:Central Nervous System Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007649:Ketamine / Q000494:pharmacology; D008253:Macaca mulatta; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology*; D016202:N-Methylaspartate / Q000378:metabolism; D009483:Neuropsychological Tests; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D065852:Spatial Memory / Q000187:drug effects / Q000502:physiology*; D013764:Tetrahydronaphthalenes / Q000493:pharmacokinetics / Q000494:pharmacology
D001549:Benzamides; D002250:Carbon Radioisotopes; D002491:Central Nervous System Agents; D018691:Excitatory Amino Acid Antagonists; C561922:GSK 931145; D050487:Glycine Plasma Membrane Transport Proteins; C520612:N-methyl-N-(6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)aminomethylcarboxylic acid; D019275:Radiopharmaceuticals; D013764:Tetrahydronaphthalenes; D016202:N-Methylaspartate; D007649:Ketamine