title: Modulation of NMDA receptor function by inhibition of D-amino acid oxidase in rodent brain.
abstract: Observations that N-Methyl-D-Aspartate (NMDA) antagonists produce symptoms in humans that are similar to those seen in schizophrenia have led to the current hypothesis that schizophrenia might result from NMDA receptor hypofunction. Inhibition of D-amino acid oxidase (DAAO), the enzyme responsible for degradation of D-serine, should lead to increased levels of this co-agonist at the NMDA receptor, and thereby provide a therapeutic approach to schizophrenia. We have profiled some of the preclinical biochemical, electrophysiological, and behavioral consequences of administering potent and selective inhibitors of DAAO to rodents to begin to test this hypothesis. Inhibition of DAAO activity resulted in a significant dose and time dependent increase in D-serine only in the cerebellum, although a time delay was observed between peak plasma or brain drug concentration and cerebellum D-serine response. Pharmacokinetic/pharmacodynamic (PK/PD) modeling employing a mechanism-based indirect response model was used to characterize the correlation between free brain drug concentration and D-serine accumulation. DAAO inhibitors had little or no activity in rodent models considered predictive for antipsychotic activity. The inhibitors did, however, affect cortical activity in the Mescaline-Induced Scratching model, produced a modest but significant increase in NMDA receptor-mediated synaptic currents in primary neuronal cultures from rat hippocampus, and resulted in a significant increase in evoked hippocampal theta rhythm, an in vivo electrophysiological model of hippocampal activity. These findings demonstrate that although DAAO inhibition did not cause a measurable increase in D-serine in forebrain, it did affect hippocampal and cortical activity, possibly through augmentation of NMDA receptor-mediated currents.
authors.affiliation: Neuroscience Research Unit, Pfizer Inc, Groton, CT 06340, USA. Christine.a.strick@pfizer.com
authors.forename: Christine A
authors.initials: CA
authors.lastname: Strick
authors.forename: Cheryl
authors.initials: C
authors.lastname: Li
authors.forename: Liam
authors.initials: L
authors.lastname: Scott
authors.forename: Brian
authors.initials: B
authors.lastname: Harvey
authors.forename: Mihály
authors.initials: M
authors.lastname: Hajós
authors.forename: Stefanus J
authors.initials: SJ
authors.lastname: Steyn
authors.forename: Mary A
authors.initials: MA
authors.lastname: Piotrowski
authors.forename: Larry C
authors.initials: LC
authors.lastname: James
authors.forename: James T
authors.initials: JT
authors.lastname: Downs
authors.forename: Brian
authors.initials: B
authors.lastname: Rago
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Becker
authors.forename: Ayman
authors.initials: A
authors.lastname: El-Kattan
authors.forename: Youfen
authors.initials: Y
authors.lastname: Xu
authors.forename: Alan H
authors.initials: AH
authors.lastname: Ganong
authors.forename: F David
authors.initials: FD
authors.lastname: Tingley
authors.forename: Andres D
authors.initials: AD
authors.lastname: Ramirez
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Seymour
authors.forename: Victor
authors.initials: V
authors.lastname: Guanowsky
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Majchrzak
authors.forename: Carol B
authors.initials: CB
authors.lastname: Fox
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Schmidt
authors.forename: Allen J
authors.initials: AJ
authors.lastname: Duplantier
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D000697:Central Nervous System Stimulants / Q000378:metabolism / Q000494:pharmacology; D006152:Cyclic GMP / Q000032:analysis / Q000096:biosynthesis; D003605:D-Amino-Acid Oxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D004353:Drug Evaluation, Preclinical; D004569:Electroencephalography; D006185:Habituation, Psychophysiologic / Q000187:drug effects / Q000502:physiology; D006246:Harmaline / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology*; D008635:Mescaline / Q000494:pharmacology; D051379:Mice; D055369:Miniature Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D008954:Models, Biological; D008956:Models, Chemical; D058990:Molecular Targeted Therapy; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D011537:Pruritus / Q000139:chemically induced / Q000517:prevention & control; D011595:Psychomotor Agitation / Q000188:drug therapy*; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism*; D055139:Sensory Gating / Q000187:drug effects / Q000502:physiology; D012694:Serine / Q000097:blood; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
chemical_list: D000697:Central Nervous System Stimulants; D016194:Receptors, N-Methyl-D-Aspartate; D017366:Serotonin Receptor Agonists; D012694:Serine; D006246:Harmaline; C485958:Dao1 protein, mouse; D003605:D-Amino-Acid Oxidase; D006152:Cyclic GMP; D008635:Mescaline