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

TitleMapping the central effects of chronic ketamine administration in an adolescent primate model by functional magnetic resonance imaging (fMRI)
Authors
Issue Date2012
PublisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/neuro
Citation
Neurotoxicology, 2012, v. 33 n. 1, p. 70-77 How to Cite?
Abstract
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.
Persistent Identifierhttp://hdl.handle.net/10722/152824
ISSN
2013 Impact Factor: 3.054
2013 SCImago Journal Rankings: 0.992
ISI Accession Number ID

 

Author Affiliations
  1. The University of Hong Kong
  2. Shandong University School of Medicine
  3. Chinese University of Hong Kong
DC FieldValueLanguage
dc.contributor.authorYu, Hen_US
dc.contributor.authorLi, Qen_US
dc.contributor.authorWang, Den_US
dc.contributor.authorShi, Len_US
dc.contributor.authorLu, Gen_US
dc.contributor.authorSun, Len_US
dc.contributor.authorWang, Len_US
dc.contributor.authorZhu, Wen_US
dc.contributor.authorMak, YTen_US
dc.contributor.authorWong, Nen_US
dc.contributor.authorWang, Y-
dc.contributor.authorPan, F-
dc.contributor.authorYew, DT-
dc.date.accessioned2012-07-16T09:49:41Z-
dc.date.available2012-07-16T09:49:41Z-
dc.date.issued2012en_US
dc.identifier.citationNeurotoxicology, 2012, v. 33 n. 1, p. 70-77en_US
dc.identifier.issn0161-813X-
dc.identifier.urihttp://hdl.handle.net/10722/152824-
dc.description.abstractKetamine, 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.-
dc.languageengen_US
dc.publisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/neuro-
dc.relation.ispartofNeurotoxicologyen_US
dc.subject.meshBrain - blood supply - drug effects-
dc.subject.meshBrain Mapping-
dc.subject.meshExcitatory Amino Acid Antagonists - administration and dosage-
dc.subject.meshKetamine - administration and dosage-
dc.subject.meshMagnetic Resonance Imaging-
dc.titleMapping the central effects of chronic ketamine administration in an adolescent primate model by functional magnetic resonance imaging (fMRI)en_US
dc.typeArticleen_US
dc.identifier.emailLi, Q: liqi@hkucc.hku.hken_US
dc.identifier.emailPan, F: panfang2003@hotmail.com-
dc.identifier.emailYew, DT: david-yew@cuhk.edu.hk-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.neuro.2011.11.001-
dc.identifier.pmid22178134-
dc.identifier.scopuseid_2-s2.0-84155176898-
dc.identifier.hkuros201989en_US
dc.identifier.volume33en_US
dc.identifier.issue1-
dc.identifier.spage70en_US
dc.identifier.epage77en_US
dc.identifier.isiWOS:000300519500009-
dc.publisher.placeNetherlands-
dc.identifier.citeulike10122616-

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