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

Yu, Hao; Li, Qi; Wang, Defeng; Shi, Lin; Lü, Gang; Sun, Lin; Wang, Li; Zhu, Wei; Mak, Y. T.; Wong, Nai-Kei; Wang, Yixiang; Pan, Fang; Yew, David T.

doi:10.1016/j.neuro.2011.11.001

Cited by 44 publications

(30 citation statements)

References 51 publications

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“…In rodents, ketamine has been shown to increase DA turnover in the nucleus accumbens (Irifune et al, 1997; Irifune et al, 1991) and the striatum (Irifune et al, 1997; Irifune et al, 1991; Ylitalo et al, 1976). In contrast, TH levels were found to be lower in the prefrontal cortex of ketamine-treated monkeys, which matched reduced DA levels in the prefrontal cortex (Yu et al, 2012). These mammalian data and the results of the present study indicate that treatment dose and duration may be responsible for varying DA levels in response to ketamine.…”

Section: Discussionmentioning

confidence: 97%

Distinct effects of ketamine and acetyl l-carnitine on the dopamine system in zebrafish

Robinson

Dumas

Cuevas

et al. 2016

Neurotoxicology and Teratology

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Ketamine, a noncompetitive N-methyl-d-aspartic acid (NMDA) receptor antagonist is commonly used as a pediatric anesthetic. We have previously shown that acetyl L-carnitine (ALCAR) prevents ketamine toxicity in zebrafish embryos. In mammals, ketamine is known to modulate the dopaminergic system. NMDA receptor antagonists are considered as promising anti-depressants, but the exact mechanism of their function is unclear. Here, we measured the levels of dopamine (DA) and its metabolites, 3, 4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the zebrafish embryos exposed to ketamine in the presence and absence of 0.5 mM ALCAR. Ketamine, at lower doses (0.1–0.3 mM), did not produce significant changes in DA, DOPAC or HVA levels in 52 h post-fertilization embryos treated for 24 h. In these embryos, tyrosine hydroxylase (TH) mRNA expression remained unchanged. However, 2 mM ketamine (internal embryo exposure levels equivalent to human anesthetic plasma concentration) significantly reduced DA level and TH mRNA indicating that DA synthesis was adversely affected. In the presence or absence of 2 mM ketamine, ALCAR showed similar effects on DA level and TH mRNA, but increased DOPAC level compared to control. ALCAR reversed 2 mM ketamine-induced reduction in HVA levels. With ALCAR alone, the expression of genes encoding the DA metabolizing enzymes, MAO (monoamine oxidase) and catechol-O-methyltransferase (COMT), was not affected. However, ketamine altered MAO mRNA expression, except at the 0.1 mM dose. COMT transcripts were reduced in the 2 mM ketamine-treated group. These distinct effects of ketamine and ALCAR on the DA system may shed some light on the mechanism on how ketamine can work as an anti-depressant, especially at sub-anesthetic doses that do not affect DA metabolism and suppress MAO gene expression.

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Section: Discussionmentioning

confidence: 97%

Distinct effects of ketamine and acetyl l-carnitine on the dopamine system in zebrafish

Robinson

Dumas

Cuevas

et al. 2016

Neurotoxicology and Teratology

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“…In adult rodents, chronic ketamine treatment produces lasting disruptions in working memory (Rushforth et al, 2011), attentional set-shifting (Nikiforuk and Popik, 2012), long-term memory (Amann et al, 2009; Featherstone et al, 2012), reversal learning (Featherstone et al, 2012) and social interaction (Becker and Grecksch, 2004; Becker et al, 2003), consistent with disruption of higher-order executive function and memory. Indeed, long-term ketamine use is associated with decreased cortical activity and increased glutamate concentration (Chatterjee et al, 2012; Yu et al, 2012). …”

Section: Introductionmentioning

confidence: 99%

Juvenile exposure to ketamine causes delayed emergence of EEG abnormalities during adulthood in mice

Featherstone

Nagy

Hahn

et al. 2014

Drug and Alcohol Dependence

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BACKGROUND Increased susceptibility to cognitive impairment or psychosis in adulthood is associated with adolescent drug abuse. Studies in adults have identified impairments in attention and memory, and changes in EEG, as common consequences of ketamine abuse. In contrast, the effects of ketamine on the juvenile brain have not been extensively tested. This is a significant omission, since abuse of ketamine is often observed within this age group. OBJECTIVES Juvenile mice (4–6 weeks of age) were administered ketamine (20 mg/kg) for 14 days. EEG was assessed in response to auditory stimulation both at one week following ketamine exposure at 7 weeks of age (juvenile) and again at 12 weeks of age (adult). EEG was analyzed for baseline activity, event-related power and event-related potentials (ERPs). RESULTS While no effects of ketamine exposure were observed during the juvenile period, significant reductions in amplitude of the P20 ERP component and event-related gamma power were seen following ketamine when re-tested as adults. In contrast, reductions in event–related theta were seen in ketamine-exposed mice at both time points. CONCLUSIONS Age related deficits in electrophysiological components such as P20 or event-related gamma may be due to an interruption of normal neural maturation. Reduction of NMDAR signaling during adolescence leads to delayed-onset disruption of gamma oscillations and the P20 component of the ERP. Further, delayed onset of impairment following adolescent ketamine abuse suggests that methods could be developed to detect and treat the early effects of drug exposure prior to the onset of disability.

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“…Since we used 2 mM ketamine that results in an internal exposure of ~8 μM [26], it is not possible to compare our results with those. In ketamine-treated monkeys, reduced dopamine levels in the prefrontal cortex [33] suggests that ketamine could adversely affect TH-IR neurons as observed in the zebrafish embryos exposed to ketamine.…”

Section: Discussionmentioning

confidence: 99%

N-acetylcysteine prevents ketamine-induced adverse effects on development, heart rate and monoaminergic neurons in zebrafish

Robinson

Dumas

et al. 2018

Neuroscience Letters

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N-acetylcysteine, a precursor molecule of glutathione, is an antioxidant. Ketamine, a pediatric anesthetic, has been implicated in cardiotoxicity and neurotoxicity including modulation of monoaminergic systems in mammals and zebrafish. Here, we show that N-acetylcysteine prevents ketamine’s adverse effects on development and monoaminergic neurons in zebrafish embryos. The effects of ketamine and N-acetylcysteine alone or in combination were measured on the heart rate, body length, brain serotonergic neurons and tyrosine hydroxylase-immunoreactive (TH-IR) neurons. In the absence of N-acetylcysteine, a concentration of ketamine that produces an internal embryo exposure level comparable to human anesthetic plasma concentrations significantly reduced heart rate and body length and those effects were prevented by N-acetylcysteine co-treatment. Ketamine also reduced the areas occupied by serotonergic neurons in the brain, whereas N-acetylcysteine co-exposure counteracted this effect. TH-IR neurons in the embryo brain and TH-IR cells in the trunk were significantly reduced with ketamine treatment, but not in the presence of N-acetylcysteine. In our continued search for compounds that can prevent ketamine toxicity, this study using specific endpoints of developmental toxicity, cardiotoxicity and neurotoxicity, demonstrates protective effects of N-acetylcysteine against ketamine’s adverse effects. This is the first study that shows the protective effects of N-acetylcysteine on ketamine-induced developmental defects of monoaminergic neurons as observed in a whole organism.

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

Cited by 44 publications

References 51 publications

Distinct effects of ketamine and acetyl l-carnitine on the dopamine system in zebrafish

Distinct effects of ketamine and acetyl l-carnitine on the dopamine system in zebrafish

Juvenile exposure to ketamine causes delayed emergence of EEG abnormalities during adulthood in mice

N-acetylcysteine prevents ketamine-induced adverse effects on development, heart rate and monoaminergic neurons in zebrafish

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