Mapping the central effects of chronic ketamine administration in an adolescent primate model by functional magnetic resonance imaging (fMRI).

Ketamine, a noncompetitive N-methyl-D-aspartic acid (NMDA) receptor antagonist, is capable of triggering excessive glutamate release and subsequent cortical excitation which may induce psychosis-like behavior and cognitive anomalies. Growing evidence suggests that acute ketamine administration can provoke dose-dependent positive and negative schizophrenia-like symptoms. While the acute effects of ketamine are primarily linked to aberrant activation of the prefrontal cortex and limbic structures with elevated glutamate and dopamine levels, the long-term effects of ketamine on brain functions and neurochemical homeostasis remain incompletely understood. In recent years, reports of ketamine abuse, especially among young individuals, have surged rapidly, with profound socioeconomic and health impacts. We herein investigated the chronic effects of ketamine on brain function integrity in an animal model of adolescent cynomolgus monkeys (Macaca fascicularis) by functional magnetic resonance imaging (fMRI). Immunohistochemical study was also conducted to examine neurochemical changes in the dopaminergic and cholinergic systems in the prefrontal cortex following chronic ketamine administration. Our results suggest that repeated exposure to ketamine markedly reduced neural activities in the ventral tegmental area, substantia nigra in midbrain, posterior cingulate cortex, and visual cortex in ketamine-challenged monkeys. In contrast, hyperfunction was observed in the striatum and entorhinal cortex. In terms of neurochemical and locomotive changes, chronically ketamine-challenged animals were found to have reduced tyrosine hydroxylase (TH) but not choline acetyltransferase (ChAT) levels in the prefrontal cortex, which was accompanied by diminished total movement compared with the controls. Importantly, the mesolimbic, mesocortical and entorhinal-striatal systems were found to be functionally vulnerable to ketamine's chronic effects. Dysfunctions of these neural circuits have been implicated in several neuropsychiatric disorders including depression, schizophrenia and attention deficit disorder (ADD). Collectively, our results support the proposition that repeated ketamine exposure can be exploited as a pharmacological paradigm for studying the central effects of ketamine relevant to neuropsychiatric disorders.

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

[2]  Feng Liu,et al.  Study of the development of fetal baboon brain using magnetic resonance imaging at 3 Tesla , 2008, NeuroImage.

[3]  E. Bullmore,et al.  Meta-analysis of diffusion tensor imaging studies in schizophrenia , 2009, Schizophrenia Research.

[4]  Mi-Sook Park,et al.  Brain substrates of craving to alcohol cues in subjects with alcohol use disorder. , 2007, Alcohol and alcoholism.

[5]  Zsolt Szabo,et al.  Quantitative PET Studies of the Serotonin Transporter in MDMA Users and Controls Using [11C]McN5652 and [11C]DASB , 2005, Neuropsychopharmacology.

[6]  A Kübler,et al.  Cocaine dependence and attention switching within and between verbal and visuospatial working memory , 2005, The European journal of neuroscience.

[7]  Emily C. Bell,et al.  Dextroamphetamine causes a change in regional brain activity in vivo during cognitive tasks: A functional magnetic resonance imaging study of blood oxygen level-dependent response , 2004, Biological Psychiatry.

[8]  P. Williamson,et al.  Duration of untreated psychosis vs. N-acetylaspartate and choline in first episode schizophrenia: a 1H magnetic resonance spectroscopy study at 4.0 Tesla , 2004, Psychiatry Research: Neuroimaging.

[9]  D. Finch,et al.  Neurophysiology and neuropharmacology of projections from entorhinal cortex to striatum in the rat , 1995, Brain Research.

[10]  K. Nakazawa,et al.  Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes , 2010, Nature Neuroscience.

[11]  Steve Williams,et al.  Ketamine and fMRI BOLD signal: Distinguishing between effects mediated by change in blood flow versus change in cognitive state , 2003, Human brain mapping.

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

[13]  W. Spooren,et al.  Effects of aripiprazole/OPC-14597 on motor activity, pharmacological models of psychosis, and brain activity in rats , 2008, Neuropharmacology.

[14]  U. Maskos The cholinergic mesopontine tegmentum is a relatively neglected nicotinic master modulator of the dopaminergic system: relevance to drugs of abuse and pathology , 2008, British journal of pharmacology.

[15]  R. Roth,et al.  Enduring cognitive deficits and cortical dopamine dysfunction in monkeys after long-term administration of phencyclidine. , 1997, Science.

[16]  Monte S. Buchsbaum,et al.  Cingulate gyrus volume and metabolism in the schizophrenia spectrum , 2004, Schizophrenia Research.

[17]  N. Volkow,et al.  Cocaine Cues and Dopamine in Dorsal Striatum: Mechanism of Craving in Cocaine Addiction , 2006, The Journal of Neuroscience.

[18]  D. Yew,et al.  A fMRI Study of Age-Related Differential Cortical Patterns During Cued Motor Movement , 2005, Brain Topography.

[19]  Mark Slifstein,et al.  Altered prefrontal dopaminergic function in chronic recreational ketamine users. , 2005, The American journal of psychiatry.

[20]  Ming D. Li,et al.  Replication and extension of association of choline acetyltransferase with nicotine dependence in European and African American smokers , 2010, Human Genetics.

[21]  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.

[22]  Fulton Crews,et al.  Adolescent cortical development: A critical period of vulnerability for addiction , 2007, Pharmacology Biochemistry and Behavior.

[23]  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.

[24]  G. Vallortigara,et al.  Possible evolutionary origins of cognitive brain lateralization , 1999, Brain Research Reviews.

[25]  M. Koch,et al.  The acoustic startle response in rats—circuits mediating evocation, inhibition and potentiation , 1997, Behavioural Brain Research.

[26]  Jiang Peng,et al.  [Mechanisms of autologous chondrocytes mass transplantation in the repair of cartilage defects of rabbits' knee]. , 2010, Zhongguo gu shang = China journal of orthopaedics and traumatology.

[27]  Wei Hao,et al.  Frontal white matter abnormalities following chronic ketamine use: a diffusion tensor imaging study. , 2010, Brain : a journal of neurology.

[28]  Marc Laruelle,et al.  Dopamine Depletion and In Vivo Binding of PET D1 Receptor Radioligands: Implications for Imaging Studies in Schizophrenia , 2003, Neuropsychopharmacology.

[29]  Jong H. Yoon,et al.  GABA Concentration Is Reduced in Visual Cortex in Schizophrenia and Correlates with Orientation-Specific Surround Suppression , 2010, The Journal of Neuroscience.

[30]  L. Heimer A new anatomical framework for neuropsychiatric disorders and drug abuse. , 2003, The American journal of psychiatry.

[31]  B. Moghaddam,et al.  Transient N-methyl-D-aspartate receptor blockade in early development causes lasting cognitive deficits relevant to schizophrenia , 2005, Biological Psychiatry.

[32]  M. H. Parks,et al.  Brain fMRI activation associated with self-paced finger tapping in chronic alcohol-dependent patients. , 2003, Alcoholism, clinical and experimental research.

[33]  D. Schulz,et al.  Prolonged effect of an anesthetic dose of ketamine on behavioral despair , 2002, Pharmacology Biochemistry and Behavior.

[34]  Leslie Muetzelfeldt,et al.  Consequences of chronic ketamine self-administration upon neurocognitive function and psychological wellbeing: a 1-year longitudinal study. , 2010, Addiction.

[35]  Ron Kikinis,et al.  Fusiform gyrus volume reduction in first-episode schizophrenia: a magnetic resonance imaging study. , 2002, Archives of general psychiatry.

[36]  John M. Pearson,et al.  Neurons in Posterior Cingulate Cortex Signal Exploratory Decisions in a Dynamic Multioption Choice Task , 2009, Current Biology.

[37]  T. Robbins,et al.  Neural systems of reinforcement for drug addiction: from actions to habits to compulsion , 2005, Nature Neuroscience.

[38]  T. Sigmundsson,et al.  Brain anatomy and sensorimotor gating in Asperger's syndrome. , 2002, Brain : a journal of neurology.

[39]  C. Karson,et al.  Decreased mesopontine choline acetyltransferase levels in schizophrenia. Correlations with cognitive functions. , 1996, Molecular and chemical neuropathology.

[40]  B. Moghaddam,et al.  NMDA Receptor Hypofunction Produces Opposite Effects on Prefrontal Cortex Interneurons and Pyramidal Neurons , 2007, The Journal of Neuroscience.

[41]  R. See,et al.  The role of dorsal vs ventral striatal pathways in cocaine-seeking behavior after prolonged abstinence in rats , 2007, Psychopharmacology.

[42]  P. Renshaw,et al.  Greater hemodynamic response to photic stimulation in schizophrenic patients: an echo planar MRI study. , 1994, The American journal of psychiatry.

[43]  Urs Meyer,et al.  Prenatal Immune Challenge Is an Environmental Risk Factor for Brain and Behavior Change Relevant to Schizophrenia: Evidence from MRI in a Mouse Model , 2009, PloS one.

[44]  M Goldstein,et al.  Immunohistochemical studies on the localization and distribution of monoamine neuron systems in the rat brain II. Tyrosine hydroxylase in the telencephalon. , 1977, Medical biology.

[45]  P. Robledo,et al.  Two discrete nucleus accumbens projection areas differentially mediate cocaine self-administration in the rat , 1993, Behavioural Brain Research.

[46]  Qi Li,et al.  Voxel-based analysis of postnatal white matter microstructure in mice exposed to immune challenge in early or late pregnancy , 2010, NeuroImage.

[47]  K. Newell,et al.  Alterations of muscarinic and GABA receptor binding in the posterior cingulate cortex in schizophrenia , 2007, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[48]  R. Gainetdinov,et al.  Glutamatergic modulation of hyperactivity in mice lacking the dopamine transporter , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[49]  C. Carter,et al.  Impairments in frontal cortical γ synchrony and cognitive control in schizophrenia , 2006, Proceedings of the National Academy of Sciences.

[50]  J. Lauriello,et al.  Longitudinal follow-up of neurochemical changes during the first year of antipsychotic treatment in schizophrenia patients with minimal previous medication exposure , 2002, Schizophrenia Research.

[51]  C. Lerman,et al.  Nicotine dependence: biology, behavior, and treatment. , 2009, Annual review of medicine.

[52]  J. Hirvonen,et al.  Ketamine does not decrease striatal dopamine D2 receptor binding in man , 2002, Psychopharmacology.

[53]  S. Sesack,et al.  Prefrontal cortical efferents in the rat synapse on unlabeled neuronal targets of catecholamine terminals in the nucleus accumbens septi and on dopamine neurons in the ventral tegmental area , 1992, The Journal of comparative neurology.

[54]  S. C. Hong,et al.  Mapping of functional organization in human visual cortex , 2000, Neurology.

[55]  Chun-sen Hsu,et al.  Ultrasonographic quantification of the endometrium during the menstrual cycle using computer-assisted analysis. , 2011, Taiwanese journal of obstetrics & gynecology.

[56]  Robert W. McCarley,et al.  A Pharmacological Model for Psychosis Based on N-methyl-D-aspartate Receptor Hypofunction: Molecular, Cellular, Functional and Behavioral Abnormalities , 2006, Biological Psychiatry.