NMDA receptor regulation of memory and behavior in humans

N‐methyl‐D‐aspartate (NMDA) receptor hypofunction is associated with a range of effects on cognition and behavior in whole animal and human studies. NMDA receptor hypofunction within the brain, which can be induced experimentally in vivo using NMDA receptor antagonist drugs, produces adverse effects on memory function. The results suggest that NMDA receptor hypofunction can preferentially affect neural mechanisms regulating the efficiency of encoding and consolidation into longer‐term storage. More pronounced NMDA receptor hypofunction can produce a clinical syndrome that includes core features of psychosis, as well as dissociation. Finally, sustained and severe underexcitation of NMDA receptors in the adult brain is associated with a neurotoxic process with well‐characterized neuropathological features. Progressive increases in severity of NMDA receptor hypofunction within the brain can produce a range of effects on brain function, involving local and distributed circuitry, which may underlie the observed changes in behavior. As the brain ages, the NMDA receptor system becomes progressively hypofunctional, potentially contributing to further age‐related decreases in memory and learning performance. Pharmacological and genomic methods for preventing NMDA receptor hypofunction, or for preventing the upstream or downstream consequences modeled by treatment with NMDA antagonists, may be applicable to the prevention and treatment of memory and behavioral dysfunction in a variety of neuropsychiatric disease conditions. Hippocampus 2001;11:529–542. © 2001 Wiley‐Liss, Inc.

[1]  D. X. Freedman.  On the use and abuse of LSD. , 1968, Archives of general psychiatry.

[2]  T. Kammer,et al.  Prefrontal activation during a nonspatial working memory task , 1996, NeuroImage.

[3]  R. Erard,et al.  The PCP psychosis: prolonged intoxication or drug-precipitated functional illness? , 1980, Journal of psychedelic drugs.

[4]  S. Anand,et al.  Phencyclidine poisoning in young children. , 1980, The Journal of pediatrics.

[5]  Robert C. Malenka,et al.  Synaptic plasticity in the hippocampus: LTP and LTD , 1994, Cell.

[6]  J. Miller,et al.  Increased neocortical neurofibrillary tangle density in subjects with Alzheimer disease and psychosis. , 2000, Archives of general psychiatry.

[7]  R. Wyatt,et al.  The psychedelic model of schizophrenia: the case of N,N-dimethyltryptamine. , 1976, The American journal of psychiatry.

[8]  M Laruelle,et al.  Alterations of benzodiazepine receptors in type II alcoholic subjects measured with SPECT and [123I]iomazenil. , 1998, The American journal of psychiatry.

[9]  S. Potkin,et al.  An open trial of glycine as an adjunct to neuroleptics in chronic treatment-refractory schizophrenics. , 1990, Journal of clinical psychopharmacology.

[10]  J. Olney,et al.  Excitotoxic amino acids and neuropsychiatric disorders. , 1990, Annual review of pharmacology and toxicology.

[11]  J. Olney,et al.  NMDA antagonist neurotoxicity: mechanism and prevention. , 1991, Science.

[12]  G. Rosenbaum,et al.  Study of a new schizophrenomimetic drug; sernyl. , 1959, A.M.A. archives of neurology and psychiatry.

[13]  D. Cyril D’Souza,et al.  Interactive effects of subanesthetic ketamine and subhypnotic lorazepam in humans , 1998, Psychopharmacology.

[14]  D. Javitt,et al.  Amelioration of negative symptoms in schizophrenia by glycine. , 1994, The American journal of psychiatry.

[15]  J. Krystal,et al.  Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[16]  C. Cotman,et al.  Age-related changes in excitatory amino acid receptors in two mouse strains , 1993, Neurobiology of Aging.

[17]  B. Sokolov,et al.  Expression of NMDAR1, GluR1, GluR7, and KA1 Glutamate Receptor mRNAs Is Decreased in Frontal Cortex of “Neuroleptic‐Free” Schizophrenics: Evidence on Reversible Up‐Regulation by Typical Neuroleptics , 1998, Journal of neurochemistry.

[18]  E. Shimizu,et al.  Genetic enhancement of learning and memory in mice , 1999, Nature.

[19]  R. Waziri.  Glycine Therapy of Schizophrenia , 1988, Biological Psychiatry.

[20]  R Freedman,et al.  Schizophrenia, sensory gating, and nicotinic receptors. , 1998, Schizophrenia bulletin.

[21]  J. Olney,et al.  Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. , 1989, Science.

[22]  D. Goff.  Dr. Goff Replies , 1995 .

[23]  T. Bliss,et al.  Synaptic plasticity in the hippocampus , 1979, Trends in Neurosciences.

[24]  J. Jonides,et al.  Dissociating verbal and spatial working memory using PET. , 1996, Cerebral cortex.

[25]  B. Sakmann,et al.  Developmental and regional expression in the rat brain and functional properties of four NMDA receptors , 1994, Neuron.

[26]  G. Ellison,et al.  Competitive and non-competitive NMDA antagonists induce similar limbic degeneration. , 1994, Neuroreport.

[27]  J. M. Moerschbaecher,et al.  Phenycyclidine in combination with d-amphetamine: Differential effects on acquisition and performance of response chains in monkeys , 1984, Pharmacology Biochemistry and Behavior.

[28]  Selective impairment of long-term but not short-term conditional fear by the N-methyl-D-aspartate antagonist APV. , 1992 .

[29]  J. Olney,et al.  Glutamate receptor dysfunction and schizophrenia. , 1995, Archives of general psychiatry.

[30]  A. Malhotra,et al.  Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[31]  J. Newcomer,et al.  Glutamatergic transmission: Therapeutic prospects for schizophrenia and Alzheimer’s disease , 2001 .

[32]  H. Beech,et al.  The effect of 1-arylcylohexylamine (sernyl) on twelve normal volunteers. , 1960, The Journal of mental science.

[33]  K. Jones,et al.  Differential effects of σ and phencyclidine receptor ligands on learning , 1990 .

[34]  H. Scheinin,et al.  Dexmedetomidine Premedication Attenuates Ketamine‐induced Cardiostimulatory Effects and Postanesthetic Delirium , 1995, Anesthesiology.

[35]  G. Buzsáki,et al.  MK-801-induced neuronal damage in rats , 1997, Brain Research.

[36]  J. Olney,et al.  Olanzapine and fluperlapine mimic clozapine in preventing MK-801 neurotoxicity , 1996, Schizophrenia Research.

[37]  E. Bullmore,et al.  Neural correlates of working memory in a visual letter monitoring task: an fMRI study , 1995, Neuroreport.

[38]  J. Grotta,et al.  Safety and tolerability of the glutamate antagonist CGS 19755 (Selfotel) in patients with acute ischemic stroke. Results of a phase IIa randomized trial. , 1995, Stroke.

[39]  J. Coyle,et al.  Dose-finding trial of D-cycloserine added to neuroleptics for negative symptoms in schizophrenia. , 1995, The American journal of psychiatry.

[40]  M. Wilson,et al.  Formation of Temporal Memory Requires NMDA Receptors within CA1 Pyramidal Neurons , 2000, Neuron.

[41]  P. Herrling,et al.  d-CPPene (SDZ EAA-494)—A Competitive NMDA Antagonist: Pharmacology and Results in Humans , 1997 .

[42]  A. Grace.  Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: A hypothesis for the etiology of schizophrenia , 1991, Neuroscience.

[43]  Y. Jan,et al.  Changing subunit composition of heteromeric NMDA receptors during development of rat cortex , 1994, Nature.

[44]  M. Fanselow,et al.  Effects of amygdala, hippocampus, and periaqueductal gray lesions on short- and long-term contextual fear. , 1993, Behavioral neuroscience.

[45]  J. Krystal,et al.  Attenuation of the neuropsychiatric effects of ketamine with lamotrigine: support for hyperglutamatergic effects of N-methyl-D-aspartate receptor antagonists. , 2000, Archives of general psychiatry.

[46]  M. Johnstone,et al.  Sernyl (CI-395) in clinical anaesthesia. , 1959, British journal of anaesthesia.

[47]  S. Nakanishi.  Molecular diversity of glutamate receptors and implications for brain function. , 1992, Science.

[48]  J. Morrison,et al.  Circuit-specific alterations of N-methyl-D-aspartate receptor subunit 1 in the dentate gyrus of aged monkeys. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[49]  Marc G Caron,et al.  Mice with Reduced NMDA Receptor Expression Display Behaviors Related to Schizophrenia , 1999, Cell.

[50]  K. Lees,et al.  Effects of prolonged infusions of the NMDA antagonist aptiganel hydrochloride (CNS 1102) in normal volunteers. , 1997, Clinical neuropharmacology.

[51]  D. Ingram,et al.  NMDA receptor channel antagonism by dizocilpine (MK-801) impairs performance of rats in aversively motivated complex maze tasks , 1991, Pharmacology Biochemistry and Behavior.

[52]  L. Goodman,et al.  The Pharmacological Basis of Therapeutics , 1941 .

[53]  G. Rosenbaum,et al.  Model psychoses and schizophrenia. , 1962, The American journal of psychiatry.

[54]  J. Kleinman,et al.  Abnormal excitatory neurotransmitter metabolism in schizophrenic brains. , 1995, Archives of general psychiatry.

[55]  G. Carmignoto,et al.  Activity-dependent decrease in NMDA receptor responses during development of the visual cortex. , 1992, Science.

[56]  J. Olney,et al.  Excitotoxic neurodegeneration in Alzheimer disease. New hypothesis and new therapeutic strategies. , 1997, Archives of neurology.

[57]  R. Biersner,et al.  Attention, Learning, and Personality During Ketamine Emergence: A Pilot Study , 1975, Anesthesia and analgesia.

[58]  K. I. Blum,et al.  Impaired Hippocampal Representation of Space in CA1-Specific NMDAR1 Knockout Mice , 1996, Cell.

[59]  G. Handelmann,et al.  Selective memory impairment by phencyclidine in rats. , 1987, European journal of pharmacology.

[60]  S. Kapur,et al.  Does fast dissociation from the dopamine d(2) receptor explain the action of atypical antipsychotics?: A new hypothesis. , 2001, The American journal of psychiatry.

[61]  J. Newcomer,et al.  The glutamate synapse in neuropsychiatric disorders. Focus on schizophrenia and Alzheimer's disease. , 1998, Progress in brain research.

[62]  J. Olney,et al.  Serotonergic Agents That Activate 5HT2A Receptors Prevent NMDA Antagonist Neurotoxicity , 1998, Neuropsychopharmacology.

[63]  S. Deutsch,et al.  A "glutamatergic hypothesis" of schizophrenia. Rationale for pharmacotherapy with glycine. , 1989, Clinical neuropharmacology.

[64]  S. Fahrbach,et al.  Demonstration of motoneuron-12 sparing in cultured Manduca sexta ventral nerve cords. , 1992, Journal of neurobiology.

[65]  M. Fanselow,et al.  The benzodiazepine inverse agonist DMCM as an unconditional stimulus for fear-induced analgesia: implications for the role of GABAA receptors in fear-related behavior. , 1992, Behavioral neuroscience.

[66]  M. Segal,et al.  Hippocampal Synaptic Plasticity in Mice Overexpressing an Embryonic Subunit of the NMDA Receptor , 1998, The Journal of Neuroscience.

[67]  M. Lazdunski,et al.  Interaction of phencyclidine ("angel dust") with a specific receptor in rat brain membranes. , 1979, Proceedings of the National Academy of Sciences of the United States of America.

[68]  P. Stanton,et al.  Long-term potentiation and N-methyl-d-aspartate receptors: Foundations of memory and neurologic disease? , 1995, Neuroscience & Biobehavioral Reviews.

[69]  Ronald W. Skelton,et al.  The neuropharmacological and neurochemical basis of place learning in the Morris water maze , 1993, Brain Research Reviews.

[70]  Robert H. Perry,et al.  [3H]MK-801 binding to the NMDA receptor complex, and its modulation in human frontal cortex during development and aging , 1992, Brain Research.

[71]  P. E. Gold,et al.  Effects of the novel NMDA antagonist, NPC 12626, on long-term potentiation, learning and memory , 1991, Brain Research.

[72]  Herbert Weingartner,et al.  NMDA Receptor Function and Human Cognition: The Effects of Ketamine in Healthy Volunteers , 1996, Neuropsychopharmacology.

[73]  S. Heinemann,et al.  Cloned glutamate receptors. , 1994, Annual review of neuroscience.

[74]  A. Carlsson,et al.  EFFECT OF CHLORPROMAZINE OR HALOPERIDOL ON FORMATION OF 3METHOXYTYRAMINE AND NORMETANEPHRINE IN MOUSE BRAIN. , 2009, Acta pharmacologica et toxicologica.

[75]  Justin A. Harris,et al.  ATTENTION, LEARNING, AND PERSONALITY DURING KETAMINE EMERGENCE , 1975 .

[76]  J. Olney,et al.  Disseminated Corticolimbic Neuronal Degeneration Induced in Rat Brain by MK-801: Potential Relevance to Alzheimer's Disease , 1998, Neurobiology of Disease.

[77]  D J Healy,et al.  Ionotropic glutamate receptor binding and subunit mRNA expression in thalamic nuclei in schizophrenia. , 2000, The American journal of psychiatry.

[78]  J. Goodhouse,et al.  Enrichment induces structural changes and recovery from nonspatial memory deficits in CA1 NMDAR1-knockout mice , 2000, Nature Neuroscience.

[79]  E F Domino,et al.  Dissociative Anesthesia: Further Pharmacologic Studies and First Clinical Experience with the Phencyclidine Derivative Cl‐581 , 1966, Anesthesia and analgesia.

[80]  D. Choi.  Excitotoxic cell death. , 1992, Journal of neurobiology.

[81]  J. Coyle,et al.  A placebo-controlled trial of D-cycloserine added to conventional neuroleptics in patients with schizophrenia. , 1999, Archives of general psychiatry.

[82]  L. Chait,et al.  The behavioral pharmacology of phencyclidine. , 1976, Clinical toxicology.

[83]  A. Malhotra,et al.  Clozapine Blunts N-Methyl-d-Aspartate Antagonist-Induced Psychosis: A Study with Ketamine , 1997, Biological Psychiatry.

[84]  John W. Olney,et al.  NMDA receptor function, memory, and brain aging , 2000, Dialogues in clinical neuroscience.

[85]  T. Bliss,et al.  Memories of NMDA receptors and LTP , 1995, Trends in Neurosciences.

[86]  S. Hirsch,et al.  NMDA receptor mRNA correlation with antemortem cognitive impairment in schizophrenia. , 1996, Neuroreport.

[87]  Nicholas Lange,et al.  D-serine added to antipsychotics for the treatment of schizophrenia , 1998, Biological Psychiatry.

[88]  Edward E. Smith,et al.  Temporal dynamics of brain activation during a working memory task , 1997, Nature.

[89]  R. Morris,et al.  The NMDA receptor antagonist D-2-amino-5-phosphonopentanoate (D-AP5) impairs spatial learning and LTP in vivo at intracerebral concentrations comparable to those that block LTP in vitro , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[90]  D. Javitt,et al.  Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia. , 1999, Archives of general psychiatry.

[91]  J. Olney,et al.  Motor Neuron Degeneration Induced by Excitotoxin Agonists Has Features in Common with those Seen in the SOD-1 Transgenic Mouse Model of Amyotrophic Lateral Sclerosis , 1996, Journal of neuropathology and experimental neurology.

[92]  H. H. Kornhuber,et al.  Low cerebrospinal fluid glutamate in schizophrenic patients and a new hypothesis on schizophrenia , 1980, Neuroscience Letters.

[93]  H. Westenberg,et al.  Efficacy and tolerance of D-cycloserine in drug-free schizophrenic patients , 1996, Biological Psychiatry.

[94]  T. Bliss,et al.  A synaptic model of memory: long-term potentiation in the hippocampus , 1993, Nature.

[95]  E. Costa,et al.  Learning impairment in rats by N-methyl-D-aspartate receptor antagonists , 1988, Neuropharmacology.

[96]  J. Coyle,et al.  D-cycloserine added to clozapine for patients with schizophrenia. , 1996, The American journal of psychiatry.

[97]  J. Krystal,et al.  Glycine Site Agonists of the NMDA Receptor: A Review , 1995 .

[98]  G. Lynch,et al.  Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5 , 1986, Nature.

[99]  M. Laruelle,et al.  Modulation of amphetamine-induced striatal dopamine release by ketamine in humans: implications for schizophrenia , 2000, Biological Psychiatry.

[100]  W. Turski,et al.  Excitatory amino acid antagonists and memory: Effect of drugs acting at N-methyl-d-aspartate receptors in learning and memory tasks , 1990, Neuropharmacology.

[101]  R. Waziri,et al.  Evidence of glutamatergic deficiency in schizophrenia , 1991, Neuroscience Letters.

[102]  W. Abraham,et al.  Effects of the NMDA antagonists CPP and MK-801 on radial arm maze performance in rats , 1990, Pharmacology Biochemistry and Behavior.

[103]  M. Paule,et al.  Acute behavioral effects of phencyclidine on rhesus monkey performance in an operant test battery , 1995, Pharmacology Biochemistry and Behavior.

[104]  Shaul Hestrin,et al.  Activation and desensitization of glutamate-activated channels mediating fast excitatory synaptic currents in the visual cortex , 1992, Neuron.

[105]  J. Olney,et al.  Multifocal brain damage induced by phencyclidine is augmented by pilocarpine , 1997, Brain Research.

[106]  J. Olney,et al.  Antipsychotic drugs block phencyclidine receptor-mediated neurotoxicity , 1993, Biological Psychiatry.

[107]  J. Krystal,et al.  Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. , 1994, Archives of general psychiatry.

[108]  Bita Moghaddam,et al.  Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex , 1997, The Journal of Neuroscience.

[109]  E. Shimizu,et al.  NMDA receptor-dependent synaptic reinforcement as a crucial process for memory consolidation. , 2000, Science.

[110]  Bert Sakmann,et al.  Heteromeric NMDA Receptors: Molecular and Functional Distinction of Subtypes , 1992, Science.

[111]  E. Butelman.  A novel NMDA antagonist, MK-801, impairs performance in a hippocampal-dependent spatial learning task , 1989, Pharmacology Biochemistry and Behavior.

[112]  H. Tilson,et al.  MK-801 impedes the acquisition of a spatial memory task in rats , 1990, Pharmacology Biochemistry and Behavior.

[113]  R. Gonzales,et al.  N-methyl-D-aspartate mediated responses decrease with age in Fischer 344 rat brain , 1991, Neurobiology of Aging.

[114]  D. Cyril D’Souza,et al.  Interactive effects of subanesthetic ketamine and haloperidol in healthy humans , 1999, Psychopharmacology.

[115]  J. Olney,et al.  α2 Adrenergic Agonists Prevent MK-801 Neurotoxicity , 1995, Neuropsychopharmacology.

[116]  K. Magnusson,et al.  The aging of the NMDA receptor complex. , 1998, Frontiers in bioscience : a journal and virtual library.

[117]  M. Pontecorvo,et al.  N-methyl-D-aspartate antagonists and working memory performance: comparison with the effects of scopolamine, propranolol, diazepam, and phenylisopropyladenosine. , 1991, Behavioral neuroscience.

[118]  G. Rosenbaum,et al.  Comparison of sernyl with other drugs: simulation of schizophrenic performance with sernyl, LSD-25, and amobarbital (amytal) sodium; I. Attention, motor function, and proprioception. , 1959, A.M.A. archives of general psychiatry.

[119]  J. Olney,et al.  Excessive cerebrocortical release of acetylcholine induced by NMDA antagonists is reduced by GABAergic and α2-adrenergic agonists , 1999, Molecular Psychiatry.

[120]  G. Rosenbaum,et al.  Comparison of phencyclidine hydrochloride (Sernyl) with other drugs. Simulation of schizophrenic performance with phencyclidine hydrochloride (Sernyl), lysergic acid diethylamide (LSD-25), and amobarbital (Amytal) sodium; II. Symbolic and sequential thinking. , 1962, Archives of general psychiatry.

[121]  P. Jatlow,et al.  Early Neuroleptic Response: Clinical Profiles and Plasma Catecholamine Metabolites , 1987, Journal of clinical psychopharmacology.

[122]  S. Potkin,et al.  Selective alterations in gene expression for NMDA receptor subunits in prefrontal cortex of schizophrenics , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[123]  M. Welch,et al.  PCP Intoxication in Young Children and Infants , 1980, Clinical pediatrics.

[124]  B. Angrist,et al.  The phenomenology of experimentally induced amphetamine psychosis--preliminary observations. , 1970, Biological psychiatry.

[125]  M. Laruelle,et al.  Increased dopamine transmission in schizophrenia: relationship to illness phases , 1999, Biological Psychiatry.

[126]  E. Buffalo,et al.  Acute behavioral effects of MK-801 in rhesus monkeys: Assessment using an operant test battery , 1994, Pharmacology Biochemistry and Behavior.

[127]  J. Olney,et al.  Isoflurane and Propofol Block Neurotoxicity Caused by MK-801 in the Rat Posterior Cingulate/Retrosplenial Cortex , 1997, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[128]  J. Sharp,et al.  DNQX inhibits phencyclidine (PCP) and ketamine induction of the hsp70 heat shock gene in the rat cingulate and retrosplenial cortex , 1995, Brain Research.

[129]  H. Kinoshita,et al.  MK-801 increases endogenous acetylcholine release in the rat parietal cortex: a study using brain microdialysis , 1993, Neuroscience Letters.

[130]  R. Gur,et al.  Neuropsychological function in schizophrenia. Selective impairment in memory and learning. , 1991, Archives of general psychiatry.

[131]  Joseph T. Coyle,et al.  The Glutamatergic Dysfunction Hypothesis for Schizophrenia , 1996, Harvard review of psychiatry.

[132]  R. Conley,et al.  Ionotropic glutamate receptors and expression of N-methyl-D-aspartate receptor subunits in subregions of human hippocampus: effects of schizophrenia. , 2000, The American journal of psychiatry.

[133]  F. Sharp,et al.  Phencyclidine induction of the hsp70 stress gene in injured pyramidal neurons is mediated via multiple receptors and voltage gated calcium channels , 1994, Neuroscience.

[134]  B. J. Casey,et al.  Activation of the prefrontal cortex in a nonspatial working memory task with functional MRI , 1994, Human brain mapping.

[135]  H. Nyman.  Neuropsychological function in schizophrenia , 2002, European Psychiatry.

[136]  D. Javitt,et al.  Recent advances in the phencyclidine model of schizophrenia. , 1991, The American journal of psychiatry.

[137]  F. Handa,et al.  Effects of oral clonidine premedication on side effects of intravenous ketamine anesthesia: a randomized, double-blind, placebo-controlled study. , 2000, Journal of clinical anesthesia.

[138]  S. Tonegawa,et al.  The Essential Role of Hippocampal CA1 NMDA Receptor–Dependent Synaptic Plasticity in Spatial Memory , 1996, Cell.

[139]  S. Oja,et al.  Dizocilpine binding to cerebral cortical membranes from developing and ageing mice , 1995, Mechanisms of Ageing and Development.

[140]  D. Reich,et al.  Ketamine: an update on the first twenty-five years of clinical experience , 1989, Canadian journal of anaesthesia = Journal canadien d'anesthesie.

[141]  D. Lodge,et al.  Effects of phencyclidine on excitatory amino acid activation of spinal interneurones in the cat. , 1982, European journal of pharmacology.

[142]  T. Gordh,et al.  The NMDA-receptor antagonist CPP abolishes neurogenic ‘wind-up pain’ after intrathecal administration in humans , 1992, Pain.

[143]  Tamara Hershey,et al.  Ketamine-Induced NMDA Receptor Hypofunction as a Model of Memory Impairment and Psychosis , 1999, Neuropsychopharmacology.

[144]  D. Price,et al.  Loss of NMDA, but not GABA-A, binding in the brains of aged rats and monkeys , 1991, Neurobiology of Aging.

[145]  J. Mastropaolo,et al.  Effects of phencyclidine, ketamine and MDMA on complex operant behavior in monkeys , 1987, Pharmacology Biochemistry and Behavior.

[146]  Edward E. Smith,et al.  Dissociation of Storage and Rehearsal in Verbal Working Memory: Evidence From Positron Emission Tomography , 1996 .

[147]  R. Gur,et al.  Neuropsychological deficits in neuroleptic naive patients with first-episode schizophrenia. , 1994, Archives of general psychiatry.

[148]  R. Zukin,et al.  Specific [3H]phencyclidine binding in rat central nervous system. , 1979, Proceedings of the National Academy of Sciences of the United States of America.

[149]  C. Bakker,et al.  Observations on the psychotomimetic effects of Sernyl. , 1961, Comprehensive psychiatry.

[150]  A. Stelzer,et al.  Synaptic disinhibition during maintenance of long-term potentiation in the CA1 hippocampal subfield. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[151]  J. Newcomer,et al.  Glycine agonists: what can they teach us about schizophrenia? , 1999, Archives of general psychiatry.

[152]  J. Krystal,et al.  Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. , 1998, The American journal of psychiatry.

[153]  L. Bianchi,et al.  NMDA receptor antagonists decrease GABA outflow from the septum and increase acetylcholine outflow from the hippocampus: a microdialysis study , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[154]  C. Cotman,et al.  Decreased expression of N-methyl-d-aspartate receptor 1 messenger RNA in select regions of Alzheimer brain , 1997, Neuroscience.

[155]  D. Choi,et al.  Glutamate neurotoxicity and diseases of the nervous system , 1988, Neuron.

[156]  K. Jansen.  Ketamine--can chronic use impair memory? , 1990, The International journal of the addictions.

[157]  A. Levey,et al.  Selective loss of glial glutamate transporter GLT‐1 in amyotrophic lateral sclerosis , 1995, Annals of neurology.

[158]  M. Hasselmo,et al.  NMDA-dependent modulation of CA1 local circuit inhibition , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[159]  S. Gershon,et al.  Amphetamine psychosis: behavioral and biochemical aspects. , 1974, Journal of psychiatric research.

[160]  R. Davis,et al.  D-cycloserine adjuvant therapy to molindone in the treatment of schizophrenia. , 1996, Clinical neuropharmacology.

[161]  J. Coyle,et al.  Short-term and long-term effects of N-methyl-D-aspartate receptor hypofunction. , 2000, Archives of general psychiatry.

[162]  J. Olney.  Excitatory Transmitters and Neuropsychiatry Disorders , 1988 .

[163]  J. Meador-Woodruff,et al.  Glutamate receptor expression in schizophrenic brain , 2000, Brain Research Reviews.

[164]  B. Moghaddam,et al.  Corticolimbic Dopamine Neurotransmission Is Temporally Dissociated from the Cognitive and Locomotor Effects of Phencyclidine , 1998, The Journal of Neuroscience.

[165]  R. Morris.  Synaptic plasticity and learning: selective impairment of learning rats and blockade of long-term potentiation in vivo by the N-methyl-D- aspartate receptor antagonist AP5 , 1989, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[166]  R. Morris,et al.  Hippocampal synaptic plasticity and NMDA receptors: a role in information storage? , 1990, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[167]  K. Dikranian,et al.  Receptor mechanisms and circuitry underlying NMDA antagonist neurotoxicity , 2002, Molecular Psychiatry.

[168]  J. Yesavage,et al.  Acute phencyclidine (PCP) intoxication: psychopathology and prognosis. , 1978, The Journal of clinical psychiatry.

[169]  Edward E. Smith,et al.  Erratum: Dissociating verbal and spatial working memory using PET (Cerebral Cortex (January/February 1996) 6:1 (11-20)) , 1998 .

[170]  J. Dundee,et al.  CLINICAL STUDIES OF INDUCTION AGENTS XXXVII: AMNESIC ACTION OF KETAMINE , 1971, British journal of anaesthesia.

[171]  S. Dursun,et al.  The effects of clozapine on levels of total cholesterol and related lipids in serum of patients with schizophrenia: a prospective study. , 1999, Journal of psychiatry & neuroscience : JPN.

[172]  James V. Hinrichs,et al.  Ketamine: behavioral effects of subanesthetic doses. , 1984, Journal of clinical psychopharmacology.

[173]  T. Yagi,et al.  Reduced hippocampal LTP and spatial learning in mice lacking NMDA receptor ε1 subunit , 1995, Nature.

[174]  L. Iversen,et al.  Phencyclidine, dizocilpine, and cerebrocortical neurons. , 1990, Science.

[175]  L. Noble,et al.  Haloperidol prevents induction of the hsp70 heat shock gene in neurons injured by phencyclidine (PCP), MK801, and ketamine , 1992, Journal of neuroscience research.

[176]  G. Ellison.  The N-methyl-d-aspartate antagonists phencyclidine, ketamine and dizocilpine as both behavioral and anatomical models of the dementias , 1995, Brain Research Reviews.

[177]  Edward E. Smith,et al.  A Parametric Study of Prefrontal Cortex Involvement in Human Working Memory , 1996, NeuroImage.

[178]  S. Deutsch,et al.  Glycine adjuvant therapy to conventional neuroleptic treatment in schizophrenia: an open-label, pilot study. , 1989, Clinical neuropharmacology.