Ketamine: NMDA Receptors and Beyond

Zorumski, Charles F.; Izumi, Yukitoshi; Mennerick, Steven

doi:10.1523/jneurosci.1547-16.2016

Cited by 173 publications

(148 citation statements)

References 73 publications

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“…While its pharmacological profile is known to be complex 58 , the key mechanism of action of ketamine is thought to be as an uncompetitive antagonist of NMDA receptors, binding at the dizocilpine (MK-801) site 58,59 . Predicting the effect that antagonising the channel might have on the (modelled) channel decay constant is difficult.…”

Section: Ketamine Parameter Effects -Nmda Channel Decay Time Constantmentioning

confidence: 99%

Generative modelling of the thalamo-cortical circuit mechanisms underlying the neurophysiological effects of ketamine

Shaw

Muthukumaraswamy

Saxena

et al. 2019

Preprint

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Abbreviations: N-methyl-D-aspartate (NMDA), gamma-aminobuyric acid (GABA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). Model population abbreviations: Population nameAbbrv. Superficial layer pyramidal (L2/3) SP Superficial layer interneuron (L2/3) SI Spiny Stellate (Layer 4) SS Deep layer pyramidal (Layer 5) DP Deep layer interneuron (Layer 5) DI Thalamic projection pyramidal (Layer 6) TP Thalamic Reticular RT Thalamic Relay RL Abstract Cortical recordings of task-induced oscillations following subanaesthetic ketamine administration demonstrate alterations in amplitude, including increases at high-frequencies (gamma) and reductions at low frequencies (theta, alpha). To investigate the population-level interactions underlying these changes, we implemented a thalamo-cortical model capable of recapitulating broadband spectralresponses. Compared with placebo, ketamine was found to increase the decay rate of NMDA receptor currents, decrease the decay rate of GABA-B receptor currents, but had no effect on AMPA or GABA-A currents. Furthermore, ketamine decreased the inhibitory self-modulation of superficial pyramidal populations, increased the inhibitory self-modulation of inhibitory interneurons and increased the strength of the cortico-thalamic projection from layer 6 into thalamus. In-silico rectification of each of these parameters to their placebo state revealed the accompanying spectral changes. Similar broadband effects were demonstrated for the NMDA constant and intrinsic connectivity changes, whereby rectification resulted in normalising the amplitude of alpha (increased) and gamma (decreased). While supporting theories of superficial pyramidal disinhibition following ketamine administration, our results suggest a role for altered cortico-thalamic connectivity relevant to understanding ketamine induced cortical responses and potentially identifies a system-level mechanism contributing to its antidepressant effects. Sample characteristicsDetails of the sample and procedures of this study have been reported previously, see Shaw et al 2015 11 . Twenty healthy (American Society of Anaesthesiologists, physical status Class 1), nonsmoking, male volunteers with a BMI of 18-30 kg/m 2 and aged between 18 -45 took part in the study.All subjects gave informed consent, with experimental procedures approved by the UK National Research Ethics Service in South East Wales. Subjects were screened for personal history of neurological or psychiatric disease by the Mini International Neuropsychiatric Interview 34 . Exclusion criteria further included contraindications to MEG or magnetic resonance imaging (MRI), and selfreported needle phobia. Visual paradigm Subjects were presented with an annular, stationary, square-wave visual grating of spatial frequency 3 cycles per degree on a mean luminance background. Gratings were displayed 150 times, with 75 at 100% contrast and 75 at 75% contrast 35 . Grating visual angle was 8º. Subjects were instructed to focus on a small, red, continually displayed dot at the centre o...

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Section: Ketamine Parameter Effects -Nmda Channel Decay Time Constantmentioning

confidence: 99%

Generative modelling of the thalamo-cortical circuit mechanisms underlying the neurophysiological effects of ketamine

Shaw

Muthukumaraswamy

Saxena

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…For the sake of completeness, the recent discovery that intravenous ketamine works rapidly to reverse depression should be mentioned, 3 possibly by blocking N-methyl-Daspartate (NMDA)-receptor-dependent bursting activity in the hypothalamic lateral habenular nucleus. 4 Its antidepressant action may involve interaction with opioid receptors.…”

Section: Introductionmentioning

confidence: 99%

Starting ketamine for neuroprotection earlier than its current use as an anesthetic/antiepileptic drug late in refractory status epilepticus

Fujikawa

2019

Epilepsia

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Summary Ketamine is currently being used as an anesthetic/antiepileptic drug in refractory status epilepticus. To validate its use, 2 clinical trials are recruiting patients. However, preclinical studies of its use in chemically induced status epilepticus in rodents have shown that it is remarkably neuroprotective, through N‐methyl‐d‐aspartate–receptor blockade, even when given after the onset of status epilepticus. Human studies have shown that status epilepticus–induced brain damage can be caused by a glutamate analogue and that it occurs in the same brain regions as in the animal studies. We therefore propose that ketamine be started early in the course of human status epilepticus as a neuroprotectant and that it be continued until epileptic discharges are eliminated. Using it as an anesthetic/antiepileptic drug late in the course of refractory status epilepticus only ensures that it is given after widespread brain damage has occurred.

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“…Ketamine is a nonbarbiturate N‐methyl‐d‐aspartate (NMDA) antagonist that produces rapid‐acting, short‐lasting anesthesia. It produces unconsciousness with analgesia in addition to tachycardia and increased blood pressure . Xylazine is a potent partial alpha‐adrenergic agonist that can inhibit glucose‐stimulated insulin release, causing hyperglycemia .…”

Section: Introductionmentioning

confidence: 99%

Decreased cerebral blood flow and hemodynamic parameters during acute hyperglycemia in mice model observed by dual‐wavelength speckle imaging

Shemesh

Bokobza

Rozenberg

et al. 2019

Journal of Biophotonics

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In this study, we use dual-wavelength optical imaging-based laser speckle technique to assess cerebral blood flow and metabolic parameters in a mouse model of acute hyperglycemia (high blood glucose). The effect of acute glucose levels on physiological processes has been extensively described in multiple organ systems such as retina, kidney, and others. We postulated that hyperglycemia also alters brain function, which in turn can be monitored optically using dual-wavelength laser speckle imaging (DW-LSI) platform. DW-LSI is a wide-field, noncontact optical imaging modality that integrates the principles of laser flowmetry and oximetry to obtain macroscopic information such as hemoglobin concentration and blood flow. A total of eight mice (C57/BL6) were used, randomized into two groups of normoglycemia (control, n = 3) and hyperglycemia (n = 5). Hyperglycemia was induced by intraperitoneal injection of a commonly used anesthetic drug combining ketamine and xylazine (KX combo). We found that this KX combo increases blood glucose (BG) levels from 150 to 350 mg/dL, approximately, when measured 18 minutes post-administration. BG continues to increase throughout the test period, with BG reaching an average of 463 ± 20.34 mg/dL within 60 minutes. BG levels were measured every 10 minutes from tail blood using commercially available glucometer. Experimental results demonstrated reductions in cerebral blood flow (CBF) by 55%, tissue oxygen saturation (SO 2 ) by 15%, and cerebral metabolic rate of oxygen (CMRO 2 ) by 75% following acute hyperglycemia. The observed decrease in these parameters was consistent with results reported in the literature, measured by a variety of experimental techniques. Measurements with laser Doppler flowmetry (LDF) were also performed which confirmed a reduction in CBF following acute hyperglycemia. In summary, our findings indicate that acute hyperglycemia modified brain hemodynamic response and induced significant David Shemesh and Naor Bokovza contributed equally to this work.

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Ketamine: NMDA Receptors and Beyond

Cited by 173 publications

References 73 publications

Generative modelling of the thalamo-cortical circuit mechanisms underlying the neurophysiological effects of ketamine

Generative modelling of the thalamo-cortical circuit mechanisms underlying the neurophysiological effects of ketamine

Starting ketamine for neuroprotection earlier than its current use as an anesthetic/antiepileptic drug late in refractory status epilepticus

Decreased cerebral blood flow and hemodynamic parameters during acute hyperglycemia in mice model observed by dual‐wavelength speckle imaging

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