Effects of MK-801 treatment across several pre-clinical analyses including a novel assessment of brain metabolic function utilizing PET and CT fused imaging in live rats

BACKGROUND Functional imaging studies in schizophrenic patients have demonstrated metabolic brain abnormalities during cognitive tasks. This study aimed to 1) introduce a novel analysis of brain metabolic function in live animals to characterize the hypo- and hyperfrontality phenomena observed in schizophrenia and following NMDA antagonist exposure, and 2) identify a robust and representative MK-801 treatment regimen that effectively models brain metabolic abnormalities as well as a range of established behavioural abnormalities representative of schizophrenia. METHODS The validity of the MK-801 animal model was examined across several established pre-clinical tests, and a novel assessment of brain metabolic function using PET/CT fused imaging. In the present study, MK-801 was administered acutely at 0.1 mg/kg and 0.5 mg/kg, and sub-chronically at 0.5 mg/kg daily for 7 days. RESULTS Acute treatment at 0.5 mg/kg-disrupted facets of memory measured through performance in the 8-arm radial maze task and generated abnormalities in sensorimotor gating, social interaction and locomotor activity. Furthermore, this treatment regimen induced hyperfrontality (increased brain metabolic function in the prefrontal area) observed via PET/CT fused imaging in the live rat. LIMITATIONS While PET and CT fused imaging in the live rat offers a functional representation of metabolic function, more advanced PET/CT integration is required to analyze more discrete brain regions. CONCLUSION These findings provide insight on the effectiveness of the MK-801 pre-clinical model of schizophrenia and provide an optimal regimen to model schizophrenia. PET/CT fused imaging offers a highly translatable tool to assess hypo- and hyperfrontality in live animals.

[1]  Jeffrey A Lieberman,et al.  Effects of Ketamine, MK-801, and Amphetamine on Regional Brain 2-Deoxyglucose Uptake in Freely Moving Mice , 2000, Neuropsychopharmacology.

[2]  R. Miller,et al.  3H-labeled MK-801 binding to the excitatory amino acid receptor complex from rat brain is enhanced by glycine. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[3]  R. Heinrichs,et al.  Quantification of frontal and temporal lobe brain-imaging findings in schizophrenia: a meta-analysis , 2003, Psychiatry Research: Neuroimaging.

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

[5]  F. Sams-Dodd.  Effects of Continuous D-Amphetamine and Phencyclidine Administration on Social Behaviour, Stereotyped Behaviour, and Locomotor Activity in Rats , 1998, Neuropsychopharmacology.

[6]  B. Morris,et al.  Induction of Metabolic Hypofunction and Neurochemical Deficits after Chronic Intermittent Exposure to Phencyclidine: Differential Modulation by Antipsychotic Drugs , 2003, Neuropsychopharmacology.

[7]  J. Herman,et al.  Hypofrontality and cognitive impairment in schizophrenia: Dynamic single-photon tomography and neuropsychological assessment of schizophrenic brain function , 1990, Biological Psychiatry.

[8]  J. Coyle,et al.  Glutamate and Schizophrenia: Beyond the Dopamine Hypothesis , 2006, Cellular and Molecular Neurobiology.

[9]  E. Bullmore,et al.  Functional MR imaging of confounded hypofrontality , 1999, Human brain mapping.

[10]  J. Krystal,et al.  First in vivo evidence of an NMDA receptor deficit in medication-free schizophrenic patients , 2006, Molecular Psychiatry.

[11]  R. Mailman,et al.  Differential effects of clozapine and haloperidol on ketamine-induced brain metabolic activation , 1998, Brain Research.

[12]  F. Vollenweider,et al.  Metabolic hyperfrontality and psychopathology in the ketamine model of psychosis using positron emission tomography (PET) and [18F]fluorodeoxyglucose (FDG) , 1997, European Neuropsychopharmacology.

[13]  E. Wong,et al.  Quantitative autoradiography of [3H]‐MK‐801 binding sites in mammalian brain , 1988, British journal of pharmacology.

[14]  R. Sircar,et al.  The novel anticonvulsant MK-801: a potent and specific ligand of the brain phencyclidine/gd-receptor , 1987, Brain Research.

[15]  Shikha Snigdha,et al.  Animal models of cognitive dysfunction and negative symptoms of schizophrenia: focus on NMDA receptor antagonism. , 2010, Pharmacology & therapeutics.

[16]  Robert S. Astur,et al.  Spatial memory deficits in a virtual reality eight-arm radial maze in schizophrenia , 2012, Schizophrenia Research.

[17]  F. Sams-Dodd.  Phencyclidine in the Social Interaction Test: An Animal Model of Schizophrenia with Face and Predictive Validity , 1999, Reviews in the neurosciences.

[18]  A. Catafau,et al.  Prefrontal dysfunction in young acute neuroleptic-naive schizophrenic patients: A resting and activation SPECT study , 1994, Psychiatry Research: Neuroimaging.

[19]  N. Swerdlow,et al.  Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review , 2001, Psychopharmacology.

[20]  B. Morris,et al.  Subchronic and chronic PCP treatment produces temporally distinct deficits in attentional set shifting and prepulse inhibition in rats , 2008, Psychopharmacology.

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

[22]  H. Meltzer,et al.  Effect of repeated administration of phencyclidine on spatial performance in an eight-arm radial maze with delay in rats and mice , 2003, Pharmacology Biochemistry and Behavior.

[23]  C. Grillon,et al.  Startle gating deficits occur across prepulse intensities in schizophrenic patients , 1992, Biological Psychiatry.

[24]  A. Alavi,et al.  Fundamentals of PET and PET/CT imaging , 2011, Annals of the New York Academy of Sciences.

[25]  S. File.  The use of social interaction as a method for detecting anxiolytic activity of chlordiazepoxide-like drugs , 1980, Journal of Neuroscience Methods.

[26]  L. Iversen,et al.  The anticonvulsant MK-801 is a potent N-methyl-D-aspartate antagonist. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[27]  C. Tamminga,et al.  Delayed regional metabolic actions of phencyclidine. , 1993, European journal of pharmacology.

[28]  P. Seeman,et al.  Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil , 2009, Synapse.

[29]  J. A. Peters,et al.  The mechanism of action and pharmacological specificity of the anticonvulsant NMDA antagonist MK‐801: a voltage clamp study on neuronal cells in culture , 1989, British journal of pharmacology.

[30]  E. Wong,et al.  The novel anticonvulsant MK‐801 binds to the activated state of the N‐methyl‐d‐aspartate receptor in rat brain , 1987, British journal of pharmacology.

[31]  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.

[32]  M. Holahan,et al.  Comparison of the MK-801-induced increase in non-rewarded appetitive responding with dopamine agonists and locomotor activity in rats , 2013, Journal of psychopharmacology.

[33]  M. Kurachi,et al.  Long-term effects of neonatal MK-801 treatment on prepulse inhibition in young adult rats , 2009, Psychopharmacology.

[34]  J. Roder,et al.  The involvement of the NMDA receptor d-serine/glycine site in the pathophysiology and treatment of schizophrenia , 2010, Neuroscience & Biobehavioral Reviews.

[35]  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.

[36]  David S. Olton,et al.  The radial arm maze as a tool in behavioral pharmacology , 1987, Physiology & Behavior.

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

[38]  W. Carlezon,et al.  Effects of antipsychotic drugs on MK-801-induced attentional and motivational deficits in rats , 2009, Neuropharmacology.

[39]  M. Bardgett,et al.  The Effects of Clonidine on Discrete-Trial Delayed Spatial Alternation in Two Rat Models of Memory Loss , 2008, Neuropsychopharmacology.

[40]  C A Jones,et al.  Animal models of schizophrenia , 2011, British journal of pharmacology.

[41]  E. Wong,et al.  [3H]MK‐801 Labels a Site on the N‐Methyl‐D‐Aspartate Receptor Channel Complex in Rat Brain Membranes , 1988, Journal of neurochemistry.

[42]  D. Malone,et al.  Consequences of early life MK-801 administration: Long-term behavioural effects and relevance to schizophrenia research , 2012, Behavioural Brain Research.

[43]  Eleanor H. Simpson,et al.  A Possible Role for the Striatum in the Pathogenesis of the Cognitive Symptoms of Schizophrenia , 2010, Neuron.

[44]  A. Abbott.  Schizophrenia: The drug deadlock , 2010, Nature.

[45]  Janice W. Smith,et al.  Diverse and often opposite behavioural effects of NMDA receptor antagonists in rats: implications for “NMDA antagonist modelling” of schizophrenia , 2009, Psychopharmacology.

[46]  J. McGrath,et al.  Schizophrenia: a concise overview of incidence, prevalence, and mortality. , 2008, Epidemiologic reviews.

[47]  I. Nimmo-Smith,et al.  Hypofrontality in schizophrenia: a meta‐analysis of functional imaging studies , 2004, Acta psychiatrica Scandinavica.

[48]  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.

[49]  M S Buchsbaum,et al.  Glucose Metabolic Rate in Normals and Schizophrenics During the Continuous Performance Test Assessed by Positron Emission Tomography , 1990, British Journal of Psychiatry.

[50]  C. Meltzer,et al.  PET/CT: form and function. , 2007, Radiology.

[51]  B. Morris,et al.  Advancing schizophrenia drug discovery: optimizing rodent models to bridge the translational gap , 2012, Nature Reviews Drug Discovery.

[52]  Vicente Molina,et al.  Association between cerebral metabolic and structural abnormalities and cognitive performance in schizophrenia , 2009, Psychiatry Research: Neuroimaging.

[53]  D. Glahn,et al.  Beyond hypofrontality: A quantitative meta‐analysis of functional neuroimaging studies of working memory in schizophrenia , 2005, Human brain mapping.

[54]  J. Kemp,et al.  Systemic administration of MK-801 prevents N-methyl-d-aspartate-induced neuronal degeneration in rat brain , 1987, Neuroscience Letters.

[55]  I. Reynolds,et al.  Regional Variations in [3H]MK801 Binding to Rat Brain N‐Methyl‐D‐Aspartate Receptors , 1991, Journal of neurochemistry.

[56]  A. Giuffrida,et al.  Evaluation of NMDA receptor models of schizophrenia: Divergences in the behavioral effects of sub-chronic PCP and MK-801 , 2009, Behavioural Brain Research.

[57]  J. Coyle.  NMDA receptor and schizophrenia: a brief history. , 2012, Schizophrenia bulletin.

[58]  M. Ferro,et al.  Medial prefrontal cortical synapsin II knock-down induces behavioral abnormalities in the rat: Examining synapsin II in the pathophysiology of schizophrenia , 2011, Schizophrenia Research.