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Article: Mapping the central effects of chronic ketamine administration in an adolescent primate model by functional magnetic resonance imaging (fMRI)
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TitleMapping the central effects of chronic ketamine administration in an adolescent primate model by functional magnetic resonance imaging (fMRI)
 
AuthorsYu, H2
Li, Q1
Wang, D3
Shi, L3
Lu, G3
Sun, L2
Wang, L2
Zhu, W2
Mak, YT3
Wong, N1
Wang, Y3
Pan, F2
Yew, DT3
 
Issue Date2012
 
PublisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/neuro
 
CitationNeurotoxicology, 2012, v. 33 n. 1, p. 70-77 [How to Cite?]
DOI: http://dx.doi.org/10.1016/j.neuro.2011.11.001
 
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.
 
ISSN0161-813X
2013 Impact Factor: 3.054
2013 SCImago Journal Rankings: 0.992
 
DOIhttp://dx.doi.org/10.1016/j.neuro.2011.11.001
 
ISI Accession Number IDWOS:000300519500009
 
DC FieldValue
dc.contributor.authorYu, H
 
dc.contributor.authorLi, Q
 
dc.contributor.authorWang, D
 
dc.contributor.authorShi, L
 
dc.contributor.authorLu, G
 
dc.contributor.authorSun, L
 
dc.contributor.authorWang, L
 
dc.contributor.authorZhu, W
 
dc.contributor.authorMak, YT
 
dc.contributor.authorWong, N
 
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.issued2012
 
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.description.natureLink_to_subscribed_fulltext
 
dc.identifier.citationNeurotoxicology, 2012, v. 33 n. 1, p. 70-77 [How to Cite?]
DOI: http://dx.doi.org/10.1016/j.neuro.2011.11.001
 
dc.identifier.citeulike10122616
 
dc.identifier.doihttp://dx.doi.org/10.1016/j.neuro.2011.11.001
 
dc.identifier.epage77
 
dc.identifier.hkuros201989
 
dc.identifier.isiWOS:000300519500009
 
dc.identifier.issn0161-813X
2013 Impact Factor: 3.054
2013 SCImago Journal Rankings: 0.992
 
dc.identifier.issue1
 
dc.identifier.pmid22178134
 
dc.identifier.scopuseid_2-s2.0-84155176898
 
dc.identifier.spage70
 
dc.identifier.urihttp://hdl.handle.net/10722/152824
 
dc.identifier.volume33
 
dc.languageeng
 
dc.publisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/neuro
 
dc.publisher.placeNetherlands
 
dc.relation.ispartofNeurotoxicology
 
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)
 
dc.typeArticle
 
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<contributor.author>Lu, G</contributor.author>
<contributor.author>Sun, L</contributor.author>
<contributor.author>Wang, L</contributor.author>
<contributor.author>Zhu, W</contributor.author>
<contributor.author>Mak, YT</contributor.author>
<contributor.author>Wong, N</contributor.author>
<contributor.author>Wang, Y</contributor.author>
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<description.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&apos;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.</description.abstract>
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Author Affiliations
  1. The University of Hong Kong
  2. Shandong University School of Medicine
  3. Chinese University of Hong Kong