The Effects of General Anesthetics on Excitatory and Inhibitory Synaptic Transmission in Area CA1 of the Rat Hippocampus In Vitro

Wakasugi, Masahiro; Hirota, Koki; Roth, Sheldon H.; Ito, Yusuke

doi:10.1097/00000539-199903000-00039

Cited by 67 publications

(46 citation statements)

References 23 publications

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“…Previous brain slice studies have used from 0.2 ⌴ (Antkowiak 1999) to 500 ⌴ (Wakasugi et al 1999). We found propofol effects at 5 and 10 ⌴ (Figs.…”

Section: Concentration Of Propofolmentioning

confidence: 53%

“…Determination of the appropriate concentration of propofol for use in in vitro experiments, particularly brain slice experiments, has been quite difficult, with previous studies using from 0.2 ⌴ (Antkowiak 1999) to 500 ⌴ (Wakasugi et al 1999). We chose a nominal concentration of 30 ⌴ for the majority of experiments based on several considerations, including 1) the excellent correlation across a range of anesthetics (e.g., volatile and barbiturates) between in vitro anesthetic concentrations that suppress CA1 field population spikes (fPS) and clinically relevant in vivo anesthetic concentrations (MacIver 1997) coupled with our previous finding that 30 ⌴ propofol suppresses the CA1 fPS to a similar degree as inhalational anesthetics at clinical concentrations (Turnquist et al 2002); 2) the fact that the concentration of propofol in the slice at the end of our typical drug application period (40 min) is much lower than the applied bath concentration (5-30 ⌴) because steady-state propofol effects require Ͼ300 min of application (see DISCUSSION for details); and 3) the desire to use an adequate concentration of propofol to assay for several possible previously described sites of action, which exhibit somewhat lower affinities for propofol [e.g., sodium channels (Ratnakumari and Hemmings 1997;Rehberg and Duch 1999)].…”

Section: R E S U L T Smentioning

confidence: 99%

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Major Role For Tonic GABA_A Conductances in Anesthetic Suppression of Intrinsic Neuronal Excitability

Bieda

MacIver

2004

Journal of Neurophysiology

117

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Bieda, Mark C. and M. Bruce MacIver. Major role for tonic GABA A conductances in anesthetic suppression of intrinsic neuronal excitability. J Neurophysiol 92: 1658 -1667, 2004. First published May 12, 2004 10.1152/jn.00223.2004. Anesthetics appear to produce neurodepression by altering synaptic transmission and/or intrinsic neuronal excitability. Propofol, a widely used anesthetic, has proposed effects on many targets, ranging from sodium channels to GABA A inhibition. We examined effects of propofol on the intrinsic excitability of hippocampal CA1 neurons (primarily interneurons) recorded from adult rat brain slices. Propofol strongly depressed action potential production induced by DC injection, synaptic stimulation, or high-potassium solutions. Propofol-induced depression of intrinsic excitability was completely reversed by bicuculline and picrotoxin but was strychnine-insensitive, implicating GABA A but not glycine receptors. Propofol strongly enhanced inhibitory postsynaptic currents (IPSCs) and induced a tonic GABA A -mediated current. We pharmacologically differentiated tonic and phasic (synaptic) GABA A -mediated inhibition using the GABA A receptor antagonist SR95531 (gabazine). Gabazine (20 M) completely blocked both evoked and spontaneous IPSCs but failed to block the propofol-induced depression of intrinsic excitability, implicating tonic, but not phasic, GABA A inhibition. Glutamatergic synaptic responses were not altered by propofol (Յ30 M). Similar results were found in both interneurons and pyramidal cells and with the chemically unrelated anesthetic thiopental. These results suggest that suppression of CA1 neuron intrinsic excitability, by these anesthetics, is largely due to activation of tonic GABA A conductances; although other sites of action may play important roles in affecting synaptic transmission, which also can produce strong neurodepression. We propose that for some anesthetics, suppression of intrinsic excitability, mediated by tonic GABA A conductances, operates in conjunction with effects on synaptic transmission, mediated by other mechanisms, to depress hippocampal function during anesthesia.

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“…Previous brain slice studies have used from 0.2 ⌴ (Antkowiak 1999) to 500 ⌴ (Wakasugi et al 1999). We found propofol effects at 5 and 10 ⌴ (Figs.…”

Section: Concentration Of Propofolmentioning

confidence: 53%

Section: R E S U L T Smentioning

confidence: 99%

Major Role For Tonic GABA_A Conductances in Anesthetic Suppression of Intrinsic Neuronal Excitability

Bieda

MacIver

2004

Journal of Neurophysiology

117

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“…Rainey et al [6] has used it in autistic children to reduce their delirium. Midazolam is known to possess a synergistic effect with propofol [34][35][36]. Indeed, Midazolam dose did not show a statistically significant difference between groups of children but there was a significant negative correlation between it and the log propofol dose which is expected since children receiving a bigger dose of any sedative would need a relatively smaller dose of the other.…”

Section: Discussionmentioning

confidence: 93%

Variation of Anesthetic Sedation Requirements in Children Undergoing Auditory Brainstem Response (ABR) Test: A Retrospective Cross-sectional Study

Elgendy¹,

Ahmed²,

Elmorsy³

et al. 2016

J Anesth Clin Res

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“…A number of studies also implicated GABA A receptors in ketamine anesthesia (Scholfield, 1980;Gage and Robertson, 1985;Bennett et al, 1988;Irifune et al, 1992Irifune et al, , 2000Lin et al, 1992;Wakasugi et al, 1999), although these provided either indirect evidence for the action of ketamine on GABA A receptors, or the concentration of ketamine used was significantly higher than the anesthetically relevant concentration.…”

Section: Introductionmentioning

confidence: 99%

Ketamine, But Not Phencyclidine, Selectively Modulates Cerebellar GABA_AReceptors Containing α6 and δ Subunits

Hevers¹,

Hadley²,

Lüddens³

et al. 2008

J. Neurosci.

121

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Phencyclidine (PCP) and ketamine are dissociative anesthetics capable of inducing analgesia, psychomimetic behavior, and a catatonic state of unconsciousness. Despite broad similarities, there are notable differences between the clinical actions of ketamine and PCP. Ketamine has a lower incidence of adverse effects and generally produces greater CNS depression than PCP. Both noncompetitively inhibit NMDA receptors, yet there is little evidence that these drugs affect GABA A receptors, the primary target of most anesthetics. ␣6␤2/3␦ receptors are subtypes of the GABA A receptor family and are abundantly expressed in granular neurons within the adult cerebellum. Here, using an oocyte expression system, we show that at anesthetically relevant concentrations, ketamine, but not PCP, modulates ␣6␤2␦ and ␣6␤3␦ receptors. Additionally, at higher concentrations, ketamine directly activates these GABA A receptors. Comparatively, dizocilpine (MK-801 [(ϩ)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate]), a potent noncompetitive antagonist of NMDA receptors that is structurally unrelated to PCP, did not produce any effect on ␣6␤2␦ receptors. Of the recombinant GABA A receptor subtypes examined (␣1␤2, ␣1␤2␥2, ␣1␤2␦, ␣4␤2␥2, ␣4␤2␦, ␣6␤2␥2, ␣6␤2␦, and ␣6␤3␦), the actions of ketamine were unique to ␣6␤2␦ and ␣6␤3␦ receptors. In dissociated granule neurons and cerebellar slice recordings, ketamine potentiated the GABAergic conductance arising from ␣6-containing GABA A receptors, whereas PCP showed no effect. Furthermore, ketamine potentiation was absent in cerebellar granule neurons from transgenic functionally null ␣6 ؊/؊ and ␦ ؊/؊ mice. These findings suggest that the higher CNS depressant level achieved by ketamine may be the result of its selective actions on ␣6␤2/3␦ receptors.

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The Effects of General Anesthetics on Excitatory and Inhibitory Synaptic Transmission in Area CA1 of the Rat Hippocampus In Vitro

Cited by 67 publications

References 23 publications

Major Role For Tonic GABA_A Conductances in Anesthetic Suppression of Intrinsic Neuronal Excitability

Major Role For Tonic GABA_A Conductances in Anesthetic Suppression of Intrinsic Neuronal Excitability

Variation of Anesthetic Sedation Requirements in Children Undergoing Auditory Brainstem Response (ABR) Test: A Retrospective Cross-sectional Study

Ketamine, But Not Phencyclidine, Selectively Modulates Cerebellar GABA_AReceptors Containing α6 and δ Subunits

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The Effects of General Anesthetics on Excitatory and Inhibitory Synaptic Transmission in Area CA1 of the Rat Hippocampus In Vitro

Cited by 67 publications

References 23 publications

Major Role For Tonic GABAA Conductances in Anesthetic Suppression of Intrinsic Neuronal Excitability

Major Role For Tonic GABAA Conductances in Anesthetic Suppression of Intrinsic Neuronal Excitability

Variation of Anesthetic Sedation Requirements in Children Undergoing Auditory Brainstem Response (ABR) Test: A Retrospective Cross-sectional Study

Ketamine, But Not Phencyclidine, Selectively Modulates Cerebellar GABAAReceptors Containing α6 and δ Subunits

Contact Info

Product

Resources

About

Major Role For Tonic GABA_A Conductances in Anesthetic Suppression of Intrinsic Neuronal Excitability

Major Role For Tonic GABA_A Conductances in Anesthetic Suppression of Intrinsic Neuronal Excitability

Ketamine, But Not Phencyclidine, Selectively Modulates Cerebellar GABA_AReceptors Containing α6 and δ Subunits