Do NMDA receptor antagonist models of schizophrenia predict the clinical efficacy of antipsychotic drugs?

N-methyL-D-aspartate (NMDA) receptor antagonists, such as ketamine and phencyclidine, induce perceptual abnormalities, psychosis-like symptoms, and mood changes in healthy humans and patients with schizophrenia. The similarity between NMDA receptor antagonist-induced psychosis and schizophrenia has led to the widespread use of the drugs to provide models to aid the development of novel treatments for the disorder. This review investigates the predictive validity of NMDA receptor antagonist models based on a range of novel treatments that have now reached clinical trials. Furthermore, it considers the extent to which the different hypotheses that have been proposed to account for the psychotomimetic effects of NMDA receptor antagonist have been validated by the results of these trials. Finally, the review discusses some of the caveats associated with use of the models and some suggestions as to how a greater use of translational markers might ensure progress in understanding the relationship between the models and schizophrenia.

[1]  J. Neale,et al.  NAAG peptidase inhibition reduces locomotor activity and some stereotypes in the PCP model of schizophrenia via group II mGluR , 2004, Journal of neurochemistry.

[2]  John M. Davis,et al.  Dose Response and Dose Equivalence of Antipsychotics , 2004, Journal of clinical psychopharmacology.

[3]  M. Carli,et al.  The 5‐HT2A receptor antagonist M100,907 prevents extracellular glutamate rising in response to NMDA receptor blockade in the mPFC , 2004, Journal of neurochemistry.

[4]  François Y. Doré,et al.  Repeated subchronic exposure to phencyclidine elicits excessive atypical grooming in rats , 2006, Behavioural Brain Research.

[5]  I. Ninan,et al.  Modulation of the ability of clozapine to facilitate NMDA‐ and electrically evoked responses in pyramidal cells of the rat medial prefrontal cortex by dopamine: pharmacological evidence , 2003, The European journal of neuroscience.

[6]  M. Geyer,et al.  An Investigation of the Efficacy of Mood Stabilizers in Rodent Models of Prepulse Inhibition , 2005, Journal of Pharmacology and Experimental Therapeutics.

[7]  S. Dursun,et al.  Clozapine plus lamotrigine in treatment-resistant schizophrenia. , 1999, Archives of general psychiatry.

[8]  J. B. Appel,et al.  Antagonism of a PCP Drug Discrimination by Hallucinogens and Related Drugs , 2000, Neuropsychopharmacology.

[9]  P. Seeman,et al.  Dopamine receptor contribution to the action of PCP, LSD and ketamine psychotomimetics , 2005, Molecular Psychiatry.

[10]  S. J. Young,et al.  Phencyclidine-induced psychosis. , 1978, The American journal of psychiatry.

[11]  D. Lewis.  GABAergic local circuit neurons and prefrontal cortical dysfunction in schizophrenia , 2000, Brain Research Reviews.

[12]  Paul Greengard,et al.  Dopamine enhancement of NMDA currents in dissociated medium-sized striatal neurons: role of D1 receptors and DARPP-32. , 2002, Journal of neurophysiology.

[13]  Christian Grillon,et al.  Gating and habituation of the startle reflex in schizophrenic patients. , 1992 .

[14]  J. Levine,et al.  Changes in use of valproate and other mood stabilizers for patients with schizophrenia from 1994 to 1998. , 2000, Psychiatric services.

[15]  D. Cyril D’Souza,et al.  Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects , 2005, Psychopharmacology.

[16]  J. Lieberman,et al.  Blunted brain metabolic response to ketamine in mice lacking D1A dopamine receptors , 2001, Brain Research.

[17]  S. Dursun,et al.  Double-blind, placebo-controlled, crossover trial of clozapine plus glycine in refractory schizophrenia negative results. , 2005, Journal of clinical psychopharmacology.

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

[19]  J. C. Winter,et al.  Serotonergic/glutamatergic interactions: the effects of mGlu2/3 receptor ligands in rats trained with LSD and PCP as discriminative stimuli , 2004, Psychopharmacology.

[20]  T. Hamamura,et al.  M100907, a selective 5-HT(2A) receptor antagonist, attenuates phencyclidine-induced Fos expression in discrete regions of rat brain. , 2001, European journal of pharmacology.

[21]  E. Gordon,et al.  Synchronous Gamma activity: a review and contribution to an integrative neuroscience model of schizophrenia , 2003, Brain Research Reviews.

[22]  B. Moghaddam,et al.  Functional Interaction Between NMDA and mGlu5 Receptors: Effects on Working Memory, Instrumental Learning, Motor Behaviors, and Dopamine Release , 2004, Neuropsychopharmacology.

[23]  D. Javitt,et al.  Placebo-controlled trial of D-cycloserine added to conventional neuroleptics, olanzapine, or risperidone in schizophrenia. , 2002, The American journal of psychiatry.

[24]  P. Greengard,et al.  Diverse Psychotomimetics Act Through a Common Signaling Pathway , 2003, Science.

[25]  Bita Moghaddam,et al.  Activation of metabotropic glutamate 2/3 receptors reverses the effects of NMDA receptor hypofunction on prefrontal cortex unit activity in awake rats. , 2005, Journal of neurophysiology.

[26]  Stephan Heckers,et al.  Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment. , 2003, Pharmacology & therapeutics.

[27]  R. Roth,et al.  The Neuropsychopharmacology of Phencyclidine: From NMDA Receptor Hypofunction to the Dopamine Hypothesis of Schizophrenia , 1999, Neuropsychopharmacology.

[28]  S. Dursun,et al.  Gender Differences and the Effects of Ketamine in Healthy Volunteers , 2004, Journal of psychopharmacology.

[29]  P. Diemunsch,et al.  Effect of a subanesthetic dose of ketamine on memory and conscious awareness in healthy volunteers , 2000, Psychopharmacology.

[30]  U. Ungerstedt,et al.  Dopamine D1 and D2 receptor antagonism differentially modulates stimulation of striatal neurotransmitter levels by N-methyl-D-aspartic acid. , 1994, European journal of pharmacology.

[31]  M. Hunt,et al.  Ketamine Induces Dopamine-Dependent Depression of Evoked Hippocampal Activity in the Nucleus Accumbens in Freely Moving Rats , 2005, The Journal of Neuroscience.

[32]  D. Javitt,et al.  Ketamine-induced deficits in auditory and visual context-dependent processing in healthy volunteers: implications for models of cognitive deficits in schizophrenia. , 2000, Archives of general psychiatry.

[33]  Bob Oranje,et al.  The Effects of a Sub-Anaesthetic Dose of Ketamine on Human Selective Attention , 2000, Neuropsychopharmacology.

[34]  Paul J. Harrison,et al.  For Personal Use. Only Reproduce with Permission from the Lancet Publishing Group. Genes for Schizophrenia? Recent Findings and Their Pathophysiological Implications , 2022 .

[35]  M. Geyer,et al.  Prestimulus effects on human startle reflex in normals and schizophrenics. , 1978, Psychophysiology.

[36]  Masatoshi Tanaka,et al.  Involvement of serotonin 2A receptors in phencyclidine-induced disruption of prepulse inhibition of the acoustic startle in rats , 1999, Biological Psychiatry.

[37]  G. Aghajanian,et al.  Serotonin Induces Excitatory Postsynaptic Potentials in Apical Dendrites of Neocortical Pyramidal Cells , 1997, Neuropharmacology.

[38]  A. Carlsson,et al.  Glycine and D-serine decrease MK-801-induced hyperactivity in mice , 2005, Journal of Neural Transmission.

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

[40]  X. Langlois,et al.  Combined alpha2 and D2/3 receptor blockade enhances cortical glutamatergic transmission and reverses cognitive impairment in the rat. , 2005, The international journal of neuropsychopharmacology.

[41]  P. Overton,et al.  Burst firing in midbrain dopaminergic neurons , 1997, Brain Research Reviews.

[42]  D. Goff,et al.  d-Cycloserine added to risperidone in patients with primary negative symptoms of schizophrenia , 2002, Schizophrenia Research.

[43]  Y. Smith,et al.  Distribution of mGluR1α and mGluR5 immunolabeling in primate prefrontal cortex , 2003 .

[44]  L. Kochan,et al.  Adjunctive divalproex and hostility among patients with schizophrenia receiving olanzapine or risperidone. , 2004, Psychiatric services.

[45]  Hank P Jedema,et al.  Clozapine Preferentially Increases Dopamine Release in the Rhesus Monkey Prefrontal Cortex Compared with the Caudate Nucleus , 1999, Neuropsychopharmacology.

[46]  R. Anwyl,et al.  Presynaptic inhibitory action of the group II metabotropic glutamate receptor agonists, LY354740 and DCG-IV. , 1998, European journal of pharmacology.

[47]  R. Roth,et al.  Alpha-2 Adrenoceptor Activation Inhibits Phencyclidine-Induced Deficits of Spatial Working Memory in Rats , 2005, Neuropsychopharmacology.

[48]  J. Olney,et al.  New insights and new issues in developmental neurotoxicology. , 2002, Neurotoxicology.

[49]  Markus von Kienlin,et al.  Functional magnetic resonance imaging reveals similar brain activity changes in two different animal models of schizophrenia , 2005, Psychopharmacology.

[50]  A. Belger,et al.  Dissociation of ketamine effects on rule acquisition and rule implementation: possible relevance to NMDA receptor contributions to executive cognitive functions , 2000, Biological Psychiatry.

[51]  P. Ascher,et al.  Glycine potentiates the NMDA response in cultured mouse brain neurons , 1987, Nature.

[52]  T. dePaulis.  M-100907 (Aventis). , 2001 .

[53]  Hans Stassen,et al.  How specific are deficits in mismatch negativity generation to schizophrenia? , 2003, Biological Psychiatry.

[54]  U. Heresco-Levy.  Glutamatergic neurotransmission modulation and the mechanisms of antipsychotic atypicality , 2003, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[55]  Lawrence H Snyder,et al.  Effects of the NMDA Antagonist Ketamine on Task-Switching Performance: Evidence for Specific Impairments of Executive Control , 2006, Neuropsychopharmacology.

[56]  H. Shannon,et al.  Blockade of phencyclidine-induced hyperlocomotion by olanzapine, clozapine and serotonin receptor subtype selective antagonists in mice , 1997, Psychopharmacology.

[57]  J. Newcomer.  Second-Generation (Atypical) Antipsychotics and Metabolic Effects , 2005, CNS drugs.

[58]  B. Morris,et al.  PCP: from pharmacology to modelling schizophrenia. , 2005, Current opinion in pharmacology.

[59]  Hiromitsu Shimizu,et al.  A microsatellite repeat in the promoter of the N-methyl-D-aspartate receptor 2A subunit (GRIN2A) gene suppresses transcriptional activity and correlates with chronic outcome in schizophrenia. , 2003, Pharmacogenetics.

[60]  H. Lublin,et al.  Current therapy issues and unmet clinical needs in the treatment of schizophrenia: a review of the new generation antipsychotics , 2005, International clinical psychopharmacology.

[61]  K. Heekeren,et al.  Psychological Effects of (S)-Ketamine and N,N-Dimethyltryptamine (DMT): A Double-Blind, Cross-Over Study in Healthy Volunteers , 2005, Pharmacopsychiatry.

[62]  A. Hamm,et al.  Effective neuroleptic medication removes prepulse inhibition deficits in schizophrenia patients , 2000, Biological Psychiatry.

[63]  J. Coyle,et al.  The emerging role of glutamate in the pathophysiology and treatment of schizophrenia. , 2001, The American journal of psychiatry.

[64]  J. Tiihonen,et al.  Glutamatergic drugs for schizophrenia: a systematic review and meta-analysis , 2005, Schizophrenia Research.

[65]  D. Javitt,et al.  Inhibition of System A-mediated glycine transport in cortical synaptosomes by therapeutic concentrations of clozapine: implications for mechanisms of action , 2005, Molecular Psychiatry.

[66]  H. Möller,et al.  Hypermetabolic pattern in frontal cortex and other brain regions in unmedicated schizophrenia patients , 2005, European Archives of Psychiatry and Clinical Neuroscience.

[67]  R. Roth,et al.  Subchronic Phencyclidine Administration Reduces Mesoprefrontal Dopamine Utilization and Impairs Prefrontal Cortical-Dependent Cognition in the Rat , 1997, Neuropsychopharmacology.

[68]  B. Clementz,et al.  The gamma band response may account for poor P50 suppression in schizophrenia , 1997, Neuroreport.

[69]  A. Becker,et al.  Ketamine-induced changes in rat behaviour: a possible animal model of schizophrenia. Test of predictive validity , 2004, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[70]  M. Didriksen,et al.  Performance of male C57BL/6J mice and Wistar rats in the water maze following various schedules of phencyclidine treatment , 2005, Behavioural pharmacology.

[71]  T. Goldberg,et al.  Probing prefrontal function in schizophrenia with neuropsychological paradigms. , 1988, Schizophrenia bulletin.

[72]  C. Schroeder,et al.  Behavioral effects of chronic phencyclidine in monkeys. , 1999, Neuroreport.

[73]  Hilla Peretz,et al.  Ju n 20 03 Schrödinger ’ s Cat : The rules of engagement , 2003 .

[74]  Jingyi Ma,et al.  Relation between hippocampal γ waves and behavioral disturbances induced by phencyclidine and methamphetamine , 2000, Behavioural Brain Research.

[75]  H. Holcomb,et al.  Evaluating Glutamatergic Transmission in Schizophrenia , 2003, Annals of the New York Academy of Sciences.

[76]  M. Geyer,et al.  Lamotrigine prevents ketamine but not amphetamine-induced deficits in prepulse inhibition in mice , 2003, Psychopharmacology.

[77]  R. Buchanan,et al.  Diazepam treatment of early signs of exacerbation in schizophrenia. , 1999, The American journal of psychiatry.

[78]  V. Neppe.  Carbamazepine as adjunctive treatment in nonepileptic chronic inpatients with EEG temporal lobe abnormalities. , 1983, The Journal of clinical psychiatry.

[79]  F. Sams-Dodd.  Effects of diazepam, citalopram, methadone and naloxone on PCP-induced stereotyped behaviour and social isolation in the rat social interaction test , 1998, Neuroscience & Biobehavioral Reviews.

[80]  E. Gordon,et al.  "Gamma synchrony" in first-episode schizophrenia: a disorder of temporal connectivity? , 2005, The American journal of psychiatry.

[81]  A. Belger,et al.  NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development , 2003, Psychopharmacology.

[82]  J. Lieberman,et al.  Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. , 2005, The New England journal of medicine.

[83]  S. Kapur,et al.  NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D2 and serotonin 5-HT2 receptors—implications for models of schizophrenia , 2002, Molecular Psychiatry.

[84]  K. Johnson,et al.  Adaptation to chronic PCP results in hyperfunctional NMDA and hypofunctional GABAA synaptic receptors , 2002, Neuroscience.

[85]  C. Kuo,et al.  A common anticonvulsant binding site for phenytoin, carbamazepine, and lamotrigine in neuronal Na+ channels. , 1998, Molecular pharmacology.

[86]  H. Emrich,et al.  Combined Treatment of Schizophrenic Psychoses with Haloperidol and Valproate , 1998, Pharmacopsychiatry.

[87]  D. Javitt,et al.  Comparative effects of glycine and d-cycloserine on persistent negative symptoms in schizophrenia: a retrospective analysis , 2004, Schizophrenia Research.

[88]  Valproate for schizophrenia. , 2016, The Cochrane database of systematic reviews.

[89]  A. Guidotti,et al.  A GABAergic cortical deficit dominates schizophrenia pathophysiology. , 2004, Critical reviews in neurobiology.

[90]  J. Friedman.  Re: Atypical Antipsychotics Mechanisms of Action , 2003 .

[91]  A. Guidotti,et al.  GABAergic dysfunction in schizophrenia: new treatment strategies on the horizon , 2005, Psychopharmacology.

[92]  D. Goff,et al.  The potential role of lamotrigine in schizophrenia , 2005, Psychopharmacology.

[93]  J. Pierri,et al.  Altered cortical glutamate neurotransmission in schizophrenia: evidence from morphological studies of pyramidal neurons. , 2003, Annals of the New York Academy of Sciences.

[94]  J. Lieberman,et al.  Mechanisms of typical and atypical antipsychotic drug action in relation to dopamine and NMDA receptor hypofunction hypotheses of schizophrenia , 1999, Molecular Psychiatry.

[95]  Bita Moghaddam,et al.  NMDA receptor hypofunction produces concomitant firing rate potentiation and burst activity reduction in the prefrontal cortex. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[96]  Carol A. Tamminga,et al.  Subanesthetic Doses of Ketamine Stimulate Psychosis in Schizophrenia , 1995, Neuropsychopharmacology.

[97]  F. Benes,et al.  Emerging principles of altered neural circuitry in schizophrenia , 2000, Brain Research Reviews.

[98]  J. Jentsch,et al.  A low dose of the alpha2 agonist clonidine ameliorates the visual attention and spatial working memory deficits produced by phencyclidine administration to rats , 2004, Psychopharmacology.

[99]  A. Guidotti,et al.  Valproate corrects the schizophrenia-like epigenetic behavioral modifications induced by methionine in mice , 2005, Biological Psychiatry.

[100]  Nicholas Lange,et al.  Glycine transporter I inhibitor, N-Methylglycine (sarcosine), added to antipsychotics for the treatment of schizophrenia , 2004, Biological Psychiatry.

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

[102]  J. Lauriello,et al.  Effects of ketamine on anterior cingulate glutamate metabolism in healthy humans: a 4-T proton MRS study. , 2005, The American journal of psychiatry.

[103]  Charles R. Yang,et al.  Interaction of dopamine D1 and NMDA receptors mediates acute clozapine potentiation of glutamate EPSPs in rat prefrontal cortex. , 2002, Journal of neurophysiology.

[104]  B. Moghaddam,et al.  Activation of Glutamate Neurotransmission in the Prefrontal Cortex Sustains the Motoric and Dopaminergic Effects of Phencyclidine , 2003, Neuropsychopharmacology.

[105]  R. Baldessarini,et al.  Modern antipsychotic drugs: a critical overview , 2005, Canadian Medical Association Journal.

[106]  B. Langguth,et al.  Cortical excitability in neuroleptic-naive first-episode schizophrenic patients , 2004, Schizophrenia Research.

[107]  Edith Pomarol-Clotet,et al.  The Effects of a Subpsychotic Dose of Ketamine on Recognition and Source Memory for Agency: Implications for Pharmacological Modelling of Core Symptoms of Schizophrenia , 2006, Neuropsychopharmacology.

[108]  Richard S. Ehrlichman,et al.  Ketamine Produces Lasting Disruptions in Encoding of Sensory Stimuli , 2006, Journal of Pharmacology and Experimental Therapeutics.

[109]  D. Senkowski,et al.  Reduced oscillatory gamma-band responses in unmedicated schizophrenic patients indicate impaired frontal network processing , 2004, Clinical Neurophysiology.

[110]  R. Greene.  Circuit analysis of NMDAR hypofunction in the hippocampus, in vitro, and psychosis of schizophrenia † , 2001, Hippocampus.

[111]  S. Snyder,et al.  Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. , 1976, Science.

[112]  Danielle C. Turner,et al.  Impairment of specific episodic memory processes by sub-psychotic doses of ketamine: the effects of levels of processing at encoding and of the subsequent retrieval task , 2005, Psychopharmacology.

[113]  M. Sarter,et al.  Effects of acute and repeated systemic administration of ketamine on prefrontal acetylcholine release and sustained attention performance in rats , 2002, Psychopharmacology.

[114]  E. Aronica,et al.  Expression and functional role of mGluR3 and mGluR5 in human astrocytes and glioma cells: opposite regulation of glutamate transporter proteins , 2003, The European journal of neuroscience.

[115]  D. Weinberger,et al.  Cell biology of the hippocampal formation in schizophrenia , 1999, Biological Psychiatry.

[116]  David L. Braff,et al.  Information-processing deficits and thought disorder in schizophrenia. , 1994 .

[117]  E. Jodo,et al.  Activation of medial prefrontal cortex by phencyclidine is mediated via a hippocampo-prefrontal pathway. , 2005, Cerebral cortex.

[118]  W. Shi,et al.  Dendritic Glutamate-Induced Bursting in the Prefrontal Cortex: Further Characterization and Effects of Phencyclidine , 2003, Journal of Pharmacology and Experimental Therapeutics.

[119]  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.

[120]  M. Millan.  N-Methyl-d-aspartate receptors as a target for improved antipsychotic agents: novel insights and clinical perspectives , 2005, Psychopharmacology.

[121]  P. Seeman,et al.  Dopamine agonist action of phencyclidine , 2005, Synapse.

[122]  D. Daniel,et al.  Effect of Divalproex Combined with Olanzapine or Risperidone in Patients with an Acute Exacerbation of Schizophrenia , 2003, Neuropsychopharmacology.

[123]  C. Large,et al.  Investigation of the effects of lamotrigine and clozapine in improving reversal-learning impairments induced by acute phencyclidine and d-amphetamine in the rat , 2005, Psychopharmacology.

[124]  H. Holcomb,et al.  Probing the human hippocampus using rCBF: Contrasts in schizophrenia , 2001, Hippocampus.

[125]  J. Deakin,et al.  Familial and developmental abnormalities of frontal lobe function and neurochemistry in schizophrenia , 1997, Journal of psychopharmacology.

[126]  K. Davis,et al.  Metabotropic glutamate receptor protein expression in the prefrontal cortex and striatum in schizophrenia , 2005, Synapse.

[127]  S. Hjorth,et al.  Systemic PCP treatment elevates brain extracellular 5‐HT: a microdialysis study in awake rats , 1998, Neuroreport.

[128]  T. Suhara,et al.  Different roles of group I and group II metabotropic glutamate receptors on phencyclidine-induced dopamine release in the rat prefrontal cortex , 2003, Neuroscience Letters.

[129]  C. Spielewoy,et al.  Strain-Specificity in Nicotine Attenuation of Phencyclidine-Induced Disruption of Prepulse Inhibition in Mice: Relevance to Smoking in Schizophrenia Patients , 2004, Behavior genetics.

[130]  P. Conn,et al.  Metabotropic Glutamate Subtype 5 Receptors Modulate Locomotor Activity and Sensorimotor Gating in Rodents , 2003, Journal of Pharmacology and Experimental Therapeutics.

[131]  Philip Seeman,et al.  Atypical Antipsychotics: Mechanism of Action , 2002, Canadian journal of psychiatry. Revue canadienne de psychiatrie.

[132]  J. Kleinman,et al.  Comparative analysis of group II metabotropic glutamate receptor immunoreactivity in Brodmann's area 46 of the dorsolateral prefrontal cortex from patients with schizophrenia and normal subjects , 2002, Molecular Psychiatry.

[133]  G Honigfeld,et al.  Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. , 1988, Archives of general psychiatry.

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

[135]  Asla Pitkänen,et al.  Do epileptic seizures damage the brain? , 2003, Current opinion in neurology.

[136]  R. Kahn,et al.  The effects of low dose ketamine on sensory gating, neuroendocrine secretion and behavior in healthy human subjects , 1998, Psychopharmacology.

[137]  A. Lajtha,et al.  Reversal of phencyclidine-induced effects by glycine and glycine transport inhibitors , 1999, Biological Psychiatry.

[138]  D. Standaert,et al.  Dopamine D1 Receptor-Dependent Trafficking of Striatal NMDA Glutamate Receptors to the Postsynaptic Membrane , 2001, The Journal of Neuroscience.

[139]  B. Moghaddam,et al.  Bursting of prefrontal cortex neurons in awake rats is regulated by metabotropic glutamate 5 (mGlu5) receptors: rate-dependent influence and interaction with NMDA receptors. , 2006, Cerebral cortex.

[140]  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.

[141]  S. Grossman,et al.  Clozapine and haloperidol modulate N-methyl-D-aspartate- and non-N-methyl-D-aspartate receptor-mediated neurotransmission in rat prefrontal cortical neurons in vitro. , 1997, The Journal of pharmacology and experimental therapeutics.

[142]  U. Heresco-Levy.  N-Methyl-D-aspartate (NMDA) receptor-based treatment approaches in schizophrenia: the first decade. , 2000, The international journal of neuropsychopharmacology.

[143]  K. Davis,et al.  Dopamine in schizophrenia: a review and reconceptualization. , 1991, The American journal of psychiatry.

[144]  G. Steinberg,et al.  Dose Escalation Safety and Tolerance Study of the Competitive NMDA Antagonist Selfotel (CGS 19755) in Neurosurgery Patients , 1998, Clinical neuropharmacology.

[145]  J. Gewirtz,et al.  Behavioral Evidence for Interactions between a Hallucinogenic Drug and Group II Metabotropic Glutamate Receptors , 2000, Neuropsychopharmacology.

[146]  D. Javitt,et al.  Placebo-controlled trial of lamotrigine added to conventional and atypical antipsychotics in schizophrenia , 2004, Biological Psychiatry.

[147]  P. Contreras,et al.  PCP‐induced alterations in cerebral glucose utilization in rat brain: Blockade by metaphit, a PCP‐receptor‐acylating agent , 1987, Synapse.

[148]  R. Cunha,et al.  Co‐localization and functional interaction between adenosine A2A and metabotropic group 5 receptors in glutamatergic nerve terminals of the rat striatum , 2005, Journal of neurochemistry.

[149]  Daniel C. Javitt,et al.  D-serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatment-refractory schizophrenia , 2005, Biological Psychiatry.

[150]  JaneR . Taylor,et al.  Impaired Inhibition of Conditioned Responses Produced by Subchronic Administration of Phencyclidine to Rats , 2001, Neuropsychopharmacology.

[151]  B. Pouzet,et al.  Spatial Memory Deficits Induced by Perinatal Treatment of Rats with PCP and Reversal Effect of D-Serine , 2004, Neuropsychopharmacology.

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

[153]  J. Deakin,et al.  Augmenting antipsychotic treatment with lamotrigine or topiramate in patients with treatment-resistant schizophrenia: a naturalistic caseseries outcome study , 2001, Journal of psychopharmacology.

[154]  Shan Xie,et al.  Reversal of Phencyclidine-Induced Dopaminergic Dysregulation by N-Methyl-D-Aspartate Receptor/Glycine-site Agonists , 2004, Neuropsychopharmacology.

[155]  B. Moghaddam,et al.  Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. , 1998, Science.

[156]  R. Astur,et al.  Selective Cognitive Impairments Associated with NMDA Receptor Blockade in Humans , 2005, Neuropsychopharmacology.

[157]  G. Breese,et al.  Integrative role for serotonergic and glutamatergic receptor mechanisms in the action of NMDA antagonists: potential relationships to antipsychotic drug actions on NMDA antagonist responsiveness , 2002, Neuroscience & Biobehavioral Reviews.

[158]  Coward Dm,et al.  General pharmacology of clozapine. , 1992 .

[159]  J. Rainey,et al.  Prolonged psychosis attributed to phencyclidine: report of three cases. , 1975, The American journal of psychiatry.

[160]  Colin Kehrer,et al.  Effects of phencyclidines on signal transfer from the entorhinal cortex to the hippocampus in rats , 2004, Neuroscience Letters.

[161]  S. Deutsch,et al.  Interaction of stress and strain on glutamatergic neurotransmission: relevance to schizophrenia , 2003, Pharmacology Biochemistry and Behavior.

[162]  C. Balducci,et al.  The Serotonin 5-HT2A Receptors Antagonist M100907 Prevents Impairment in Attentional Performance by NMDA Receptor Blockade in the Rat Prefrontal Cortex , 2004, Neuropsychopharmacology.

[163]  B. Moghaddam,et al.  Actions of clozapine and haloperidol on the extracellular levels of excitatory amino acids in the prefrontal cortex and striatum of conscious rats , 1993, Neuroscience Letters.

[164]  U. Campbell,et al.  Metabotropic glutamate receptors: potential drug targets for the treatment of schizophrenia. , 2002, Current drug targets. CNS and neurological disorders.

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

[166]  D L Braff,et al.  Sensorimotor gating and thought disturbance measured in close temporal proximity in schizophrenic patients. , 1999, Archives of general psychiatry.

[167]  E. Castrén,et al.  Effects of NMDA-Receptor Antagonist Treatment on c-fos Expression in Rat Brain Areas Implicated in Schizophrenia , 2004, Cellular and Molecular Neurobiology.

[168]  D. B. Berman,et al.  Identification of single nucleotide polymorphisms (SNPs) and other sequence changes and estimation of nucleotide diversity in coding and flanking regions of the NMDAR1 receptor gene in schizophrenic patients , 2001, Molecular Psychiatry.

[169]  H. Schroeder,et al.  Ketamine-induced changes in rat behaviour: A possible animal model of schizophrenia , 2003, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[170]  D. Goff,et al.  Converging Evidence of NMDA Receptor Hypofunction in the Pathophysiology of Schizophrenia , 2003, Annals of the New York Academy of Sciences.

[171]  J. Deakin,et al.  A two-process theory of schizophrenia: evidence from studies in post-mortem brain. , 1997, Journal of psychiatric research.

[172]  J. Pierri,et al.  Altered Cortical Glutamate Neurotransmission in Schizophrenia , 2003 .

[173]  Neuronal Synchrony Mediated by Astrocytic Glutamate through Activation of Extrasynaptic NMDA Receptors , 2005, Neuron.

[174]  J. Newcomer,et al.  NMDA receptor hypofunction model of schizophrenia. , 1999, Journal of psychiatric research.

[175]  M. Capogna.  Distinct properties of presynaptic group II and III metabotropic glutamate receptor‐mediated inhibition of perforant pathway–CA1 EPSCs , 2004, The European journal of neuroscience.

[176]  M. Laruelle,et al.  Glutamate, dopamine, and schizophrenia: from pathophysiology to treatment. , 2003, Annals of the New York Academy of Sciences.

[177]  L. Farde,et al.  High 5HT2A receptor occupancy in M100907-treated schizophrenic patients , 2000, Psychopharmacology.

[178]  H. Holcomb,et al.  Effects of Noncompetitive NMDA Receptor Blockade on Anterior Cingulate Cerebral Blood Flow in Volunteers with Schizophrenia , 2005, Neuropsychopharmacology.

[179]  K. Davis,et al.  Metabotropic glutamate receptor mRNA expression in the schizophrenic thalamus , 2000, Biological Psychiatry.

[180]  A. Carlsson,et al.  The 5-HT2A receptor antagonist M100907 is more effective in counteracting NMDA antagonist- than dopamine agonist-induced hyperactivity in mice , 1999, Journal of Neural Transmission.

[181]  C. Tamminga,et al.  Ketamine Effects on Eye Movements , 2000, Neuropsychopharmacology.

[182]  H. Begleiter,et al.  Brain stem auditory evoked potentials in unmedicated schizophrenic patients , 1985, Biological Psychiatry.

[183]  G. Higgins,et al.  Phencyclidine Exacerbates Attentional Deficits in a Neurodevelopmental Rat Model of Schizophrenia , 2003, Neuropsychopharmacology.

[184]  Raquel E. Gur,et al.  The Effects of Ketamine Vary Among Inbred Mouse Strains and Mimic Schizophrenia for the P80, but not P20 or N40 Auditory ERP Components , 2004, Neurochemical Research.

[185]  M. Geyer,et al.  Effect of antipsychotic treatment on the prepulse inhibition deficit of mGluR5 knockout mice , 2004, Psychopharmacology.

[186]  Marc Laruelle,et al.  Modulation of Amphetamine-Induced Dopamine Release by Group II Metabotropic Glutamate Receptor Agonist LY354740 in Non-Human Primates Studied with Positron Emission Tomography , 2006, Neuropsychopharmacology.

[187]  M. Hasselmo,et al.  Gamma frequency-range abnormalities to auditory stimulation in schizophrenia. , 1999, Archives of general psychiatry.

[188]  T. Svensson.  Dysfunctional brain dopamine systems induced by psychotomimetic NMDA-receptor antagonists and the effects of antipsychotic drugs , 2000, Brain Research Reviews.

[189]  D. Schoepp,et al.  In vivo inhibition of veratridine-evoked release of striatal excitatory amino acids by the group II metabotropic glutamate receptor agonist LY354740 in rats , 1997, Neuroscience Letters.

[190]  W. Löscher,et al.  The neurobiology of antiepileptic drugs for the treatment of nonepileptic conditions , 2004, Nature Medicine.

[191]  J. Tiihonen,et al.  Lamotrigine in treatment-resistant schizophrenia: a randomized placebo-controlled crossover trial , 2003, Biological Psychiatry.

[192]  G. Marek,et al.  Preclinical pharmacology of mGlu2/3 receptor agonists: novel agents for schizophrenia? , 2002, Current drug targets. CNS and neurological disorders.

[193]  C. Normann,et al.  Effects of carbamazepine and valproate on haloperidol plasma levels and on psychopathologic outcome in schizophrenic patients. , 1999, Journal of clinical psychopharmacology.

[194]  P. Conn,et al.  A Selective Allosteric Potentiator of Metabotropic Glutamate (mGlu) 2 Receptors Has Effects Similar to an Orthosteric mGlu2/3 Receptor Agonist in Mouse Models Predictive of Antipsychotic Activity , 2005, Journal of Pharmacology and Experimental Therapeutics.

[195]  R. Steinpreis.  The behavioral and neurochemical effects of phencyclidine in humans and animals: some implications for modeling psychosis , 1996, Behavioural Brain Research.

[196]  John Garthwaite,et al.  Interaction of the antiepileptic drug lamotrigine with recombinant rat brain type IIA Na+ channels and with native Na+ channels in rat hippocampal neurones , 1995, Pflügers Archiv.

[197]  P. Seeman.  Dopamine receptor sequences. Therapeutic levels of neuroleptics occupy D2 receptors, clozapine occupies D4. , 1992, Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology.

[198]  K. Jardemark,et al.  Olanzapine and clozapine but not haloperidol reverse subchronic phencyclidine-induced functional hyperactivity of N-methyl-D-aspartate receptors in pyramidal cells of the rat medial prefrontal cortex , 2003, Neuropharmacology.

[199]  Y. Smith,et al.  Distribution of mGluR1alpha and mGluR5 immunolabeling in primate prefrontal cortex. , 2003, The Journal of comparative neurology.

[200]  G. Higgins,et al.  Examination of drug-induced and isolation-induced disruptions of prepulse inhibition as models to screen antipsychotic drugs , 1995, Psychopharmacology.

[201]  D. Weinberger,et al.  Genes, dopamine and cortical signal-to-noise ratio in schizophrenia , 2004, Trends in Neurosciences.

[202]  D. Lorrain,et al.  Effects of ketamine and n-methyl-d-aspartate on glutamate and dopamine release in the rat prefrontal cortex: modulation by a group II selective metabotropic glutamate receptor agonist LY379268 , 2003, Neuroscience.

[203]  C. Lindsley,et al.  A Novel Selective Positive Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 5 Has in Vivo Activity and Antipsychotic-Like Effects in Rat Behavioral Models , 2005, Journal of Pharmacology and Experimental Therapeutics.

[204]  B. Moghaddam,et al.  Effect of clozapine, haloperidol, or M100907 on phencyclidine-activated glutamate efflux in the prefrontal cortex , 2001, Biological Psychiatry.

[205]  M. Cooperman,et al.  Differential effects of chronic antipsychotic drug treatment on extracellular glutamate and dopamine concentrations , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[206]  Neppe Vm.  Carbamazepine as adjunctive treatment in nonepileptic chronic inpatients with EEG temporal lobe abnormalities. , 1983 .

[207]  Seiya Miyamoto,et al.  Comparison of brain metabolic activity patterns induced by ketamine, MK-801 and amphetamine in rats: support for NMDA receptor involvement in responses to subanesthetic dose of ketamine , 1999, Brain Research.

[208]  R. Corbett,et al.  Antipsychotic agents antagonize non-competitiveN-methyl-d-aspartate antagonist-induced behaviors , 1995, Psychopharmacology.

[209]  G. Reynolds,et al.  The atypical antipsychotic ziprasidone, but not haloperidol, improves phencyclidine-induced cognitive deficits in a reversal learning task in the rat , 2003, Journal of psychopharmacology.

[210]  C. Tamminga,et al.  Effects of Ketamine in Normal and Schizophrenic Volunteers , 2001, Neuropsychopharmacology.

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

[212]  D. Lorrain,et al.  Group II mGlu Receptor Activation Suppresses Norepinephrine Release in the Ventral Hippocampus and Locomotor Responses to Acute Ketamine Challenge , 2003, Neuropsychopharmacology.

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

[214]  B. Bogerts,et al.  Prepulse inhibition is different in two inbred mouse strains (CPB-K and BALB/cJ) with different hippocampal NMDA receptor densities , 2006, Behavioural Brain Research.

[215]  D. Segal,et al.  Increased startle responding in rats treated with phencyclidine. , 1984, Neurobehavioral toxicology and teratology.

[216]  D. Coward,et al.  General Pharmacology of Clozapine , 1992, British Journal of Psychiatry.

[217]  Anil K Malhotra,et al.  Ketamine-Induced Exacerbation of Psychotic Symptoms and Cognitive Impairment in Neuroleptic-Free Schizophrenics , 1997, Neuropsychopharmacology.

[218]  T. Brewerton.  The Phenomenology of Psychosis Associated with Complex Partial Seizure Disorder , 1997 .

[219]  R. Torta,et al.  Behavioral, Psychotic, and Anxiety Disorders in Epilepsy: Etiology, Clinical Features, and Therapeutic Implications , 1999, Epilepsia.

[220]  M. Laruelle,et al.  Glutamate, Dopamine, and Schizophrenia , 2003 .

[221]  D. Javitt,et al.  Double-blind, placebo-controlled, crossover trial of D-cycloserine adjuvant therapy for treatment-resistant schizophrenia. , 1998, The international journal of neuropsychopharmacology.

[222]  T. Arinami,et al.  Mutation analysis of the N-methyl-d-aspartate receptor NR1 subunit gene (GRIN1) in schizophrenia , 2000, Neuroscience Letters.

[223]  B. Moghaddam,et al.  Glutamatergic Regulation of Basal and Stimulus‐Activated Dopamine Release in the Prefrontal Cortex , 1998, Journal of neurochemistry.

[224]  G. Aghajanian,et al.  Serotonin, via 5-HT2A receptors, increases EPSCs in layer V pyramidal cells of prefrontal cortex by an asynchronous mode of glutamate release , 1999, Brain Research.

[225]  Y. Fukumaki,et al.  Identification of single-nucleotide polymorphisms in the human N-methyl-D-aspartate receptor subunit NR2D gene, GRIN2D, and association study with schizophrenia , 2005, Psychiatric genetics.

[226]  G. Collingridge,et al.  Interactions between NMDA receptors and mGlu5 receptors expressed in HEK293 cells , 2004, British journal of pharmacology.

[227]  G. Nowak,et al.  Chronic haloperidol and clozapine administration increases the number of cortical NMDA receptors in rats , 1999, Naunyn-Schmiedeberg's Archives of Pharmacology.

[228]  D. Blackwood,et al.  The genomic organisation of the metabotropic glutamate receptor subtype 5 gene, and its association with schizophrenia , 2001, Molecular Psychiatry.

[229]  E. French.  Phencyclidine and the midbrain dopamine system: electrophysiology and behavior. , 1994, Neurotoxicology and teratology.

[230]  M. Geyer,et al.  Low dose ketamine increases prepulse inhibition in healthy men , 2003, Neuropharmacology.

[231]  Erica Duncan,et al.  Clinical and Sensorimotor Gating Effects of Ketamine in Normals , 2001, Neuropsychopharmacology.

[232]  R. Buchanan,et al.  Carbamazepine maintenance treatment in outpatient schizophrenics. , 1991, Archives of general psychiatry.

[233]  A. Malhotra,et al.  Comparison of ketamine-induced thought disorder in healthy volunteers and thought disorder in schizophrenia. , 1999, The American journal of psychiatry.

[234]  M. Geyer,et al.  M100907, a Serotonin 5-HT2A Receptor Antagonist and Putative Antipsychotic, Blocks Dizocilpine-Induced Prepulse Inhibition Deficits in Sprague–Dawley and Wistar Rats , 1999, Neuropsychopharmacology.

[235]  Alan A. Wilson,et al.  Equivalent occupancy of dopamine D1 and D2 receptors with clozapine: differentiation from other atypical antipsychotics. , 2004, The American journal of psychiatry.

[236]  R. Depoortère,et al.  Neurochemical, Electrophysiological and Pharmacological Profiles of the Selective Inhibitor of the Glycine Transporter-1 SSR504734, a Potential New Type of Antipsychotic , 2005, Neuropsychopharmacology.

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