Glycine transporter inhibition reverses ketamine-induced working memory deficits.
Glycine transporter inhibitors have recently been reported to improve symptoms in patients with schizophrenia. Here we used acute ketamine in the nonhuman primate to test the effectiveness of the novel glycine transporter inhibitor, PF-3463275, in a model of cognitive dysfunction relevant to schizophrenia. PF-3463275 (0.01-0.17 mg/kg; subcutaneously) or a vehicle was given before the administration of ketamine (median dose of 1.0 mg/kg intramuscularly) or placebo (saline). Ketamine induced hallucinatory-like behaviors that were not reversed by PF-3463275. In contrast, all doses of PF-3463275 alleviated the deficit in spatial working memory induced by ketamine. Theses findings build upon those in patients by providing translational support for targeting glycine transporter in adjunctive treatment for cognitive dysfunction in schizophrenia.
Roberts
Brooke M
BM
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA.
Shaffer
Christopher L
CL
Seymour
Patricia A
PA
Schmidt
Christopher J
CJ
Williams
Graham V
GV
Castner
Stacy A
SA
D000704:Analysis of Variance; D000818:Animals; D053961:Azabicyclo Compounds / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D006212:Hallucinations / Q000139:chemically induced / Q000188:drug therapy; D007093:Imidazoles / Q000627:therapeutic use*; D008253:Macaca mulatta; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy*; D008570:Memory, Short-Term / Q000187:drug effects*; D009483:Neuropsychological Tests; D018697:Nootropic Agents / Q000627:therapeutic use*; D010087:Oxides; D011188:Potassium; D012559:Schizophrenia; D013635:Tantalum; D016896:Treatment Outcome
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; D018697:Nootropic Agents; D010087:Oxides; C516825:potassium tantalate oxide; D013635:Tantalum; D011188:Potassium