Anaesthetic modulation of synaptic transmission in the mammalian CNS

Richards, Christopher D.

doi:10.1093/bja/aef162

Cited by 55 publications

(44 citation statements)

References 83 publications

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“…Many studies suggest the involvement of ligand-gated ionic channels in mediating the action of volatile anesthetics (26,28). Also a unique structural class of K + channels with two pore-forming sequences in tandem (2P K + channels), which contributes significantly to background K + currents in neuronal tissues, has recently emerged as plausible targets for volatile anesthetics (30,31).…”

Section: Discussionmentioning

confidence: 99%

Sevoflurane Inhibition of the Slowly Activating Delayed Rectifier K+ Current in Guinea Pig Ventricular Cells

2004

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Abstract. Single ventricular cells were enzymatically isolated from guinea pig hearts and the effects of sevoflurane on the delayed rectifier K + current were investigated by the patch clamp method. The rapidly (I Kr ) and slowly activating delayed rectifier K + current (I Ks ) were isolated using chromanol 293B, a selective blocker for I Ks , a blocker for I Kr . Sevoflurane and halothane decreased I Ks in a concentration-dependent manner with an IC 50 value of 0.38 mM for sevoflurane and 1.05 mM for halothane. I Ks inhibition was characterized by suppression of maximum conductance with little effect on activation kinetics. Inhibition occurred immediately after anesthetic application and recovered upon wash-out. In contrast to the marked inhibition of I Ks , I Kr was hardly affected by sevoflurane. Under the current clamp, sevoflurane prolonged the action potential duration in a reversible manner and this effect was more marked when I Kr was inhibited by E4031. The results suggest that sevoflurane inhibits I Ks , and not I Kr , in a concentration-dependent manner at clinically relevant concentrations. The resulting prolongation of ventricular repolarization may partly account for the clinical observation of excessive QT prolongation by these anesthetics.

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Section: Discussionmentioning

confidence: 99%

Sevoflurane Inhibition of the Slowly Activating Delayed Rectifier K+ Current in Guinea Pig Ventricular Cells

2004

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“…1 It is known that glutamate and gamma-aminobutyric acid (GABA) are the most important excitatory and inhibitory neural transmitters in central nervous system. 2 In a previous study, pentobarbital potentiated GABA A receptors as a result of stabilizing the open states.…”

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confidence: 99%

“…6 In addition, pentobarbital has been shown to decrease NMDA receptor function in neurons isolated from rat olfactory brain by blocking the opening channel. 1 In the central nervous system, the prefrontal cortex (PFC) plays a key role in the generation and modulation of consciousness, 7 which depends on rapid synaptic neural transmission mediated by the GABA A receptor, the NMDA receptor and other ionotropic receptors of glutamate and GABA. 8 It has been shown that NMDA-mediated channels are closed when unconsciousness occurs in status epilepticus.…”

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confidence: 99%

Effect of thiopental sodium on N-methyl-D-aspartate-gated currents

Liu

Ti-jun

Yao

2006

Can J Anesth/J Can Anesth

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Purpose: N-methyl-D-aspartate (NMDA) receptors in the prefrontal cortex (PFC) are closely related with the excitability of pyramidal neurons and PFC function. As the effect of thiopental sodium on the central nervous system may partly result from the inhibition of PFC NMDA receptors, we investigated the effect of thiopental sodium with different concentrations on NMDA-gated currents in acutely dissociated rat PFC pyramidal neurons. We sought to determine whether thiopental sodium inhibits NMDA receptor function.Methods: Three to four week old male Sprague-Dawley rats were sacrificed and the PFC was dissected. Pyramidal neurons from the PFC were prepared and standard whole-cell patch clamp recordings were performed. Escalating concentrations from 3-1000 µM NMDA were applied 100 µm from the pyramidal cells, and the concentration in the effect compartment related to 50% effect (EC50) of NMDA was determined for the ensuing experiments. One hundred µM NMDA alone (control) or NMDA with different concentrations (10-1000 µM) of thiopental sodium were applied. After the inhibitory concentration, in 50% of NMDA effect (IC50) of thiopental sodium was established this IC50 and NMDA 3-1000 µM were applied 100 µm from the pyramidal cells. The EC50 value of NMDA under the effect of IC50 thiopental sodium was determined.Results: N-methyl-D-aspartate induced inward currents in a concentration-dependent manner, which were completely antagonized by 50 µM AP5. The maximal amplitude of NMDAinduced current was 1.15 ± 0.27 nA. The EC50 of NMDA was 53.6 ± 12.4 µM. The NMDA (100 µM)-gated current was inhibited by thiopental sodium in a concentration-dependent manner, and the IC50 of thiopental sodium was 33.6 ± 6.1 µM. Under the effect of 33.6 µM thiopental sodium, the maximal amplitude of NMDA-induced current was 0.87 ± 0.17 nA. The concentration-response curve of NMDA was shifted rightwards. The EC50 of NMDA was 128 ± 15 µM, which was greater than that of NMDA without thiopental sodium (P < 0.01). Conclusions:Thiopental sodium decreases NMDA-gated currents in acutely dissociated rat prefrontal cortical pyramidal neurons in a concentration-dependent manner. Objectif : Les récepteurs de N-méthyl-D-aspartate (NMDA) dans le cortex préfrontal (CPF) sont en lien étroit avec l'excitabilité des neurones pyramidaux et la fonction du CPF. L'effet du thio-

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“…Like other general anaesthetics, the precise molecular mechanism of action of isoflurane is not clearly understood. Although it targets multiple receptor systems, the major component of its mode of action is modulation of  -aminobutyric acid type A (GABA(A)) receptors (Richards, 2002;Ballesteros et al, 2012;Haensel et al, 2015). Despite its disadvantages, isoflurane is still a very useful agent.…”

Section: General Anaesthesia and Commonly Used Anaesthetic Regimens Fmentioning

confidence: 99%

“…Functional connectivity was not observed in the striatum in this study. This may be explained by the usage of isoflurane, which targets GABAergic receptors as a major component of its mode of action (Richards, 2002). The expression density of GABAergic receptors is very high in the striatum (Muller and Nistico, 1989), and this may lead to less retained activations in this region under isoflurane (Grandjean et al, 2014b).…”

Section: Independent Component Analysismentioning

confidence: 99%

Functional network study on the wild type and DISC1 transgenic mice

Wu¹

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Major mental disorders such as schizophrenia (SZ), bipolar disorder and major depression create a heavy social burden and remain poorly treated. Recent reports examining the genetic and molecular structure of brain disorders discovered the gene Disrupted-in-Schizophrenia 1 (DISC1) to be significantly associated with these disorders and plays a substantial role in influencing a range of shared endophenotypes underlying these disorders. This has led to a powerful gateway to explore the underlying pathology and to achieve better diagnosis and treatments of major mental diseases. Characterising the phenotypes of DISC1 in brain functions would provide valuable insights into the mechanism of how this gene influences the brain.Resting-state fMRI (rs-fMRI) is a powerful technique being applied to more than 30 different kinds of brain disorders and different species. Findings from rs-fMRI studies on humans provide ample evidence of abnormal functional patterns in patients with mental illnesses. Specifically, altered functional connectivity (FC) and network topologies are proposed to be plausible imaging endophenotypes of psychotic disorders. However, little is known about the direct effects of gene dysfunction, such as DISC1 mutations, on restingstate brain activations. One aim of this thesis is to investigate the impacts of DISC1 on variations of resting-state functional networks (RSNs) in anaesthetized mouse brains using DISC1 transgenic mice and rs-fMRI.Before characterizing disease phenotypes in mouse models, it is necessary to understand how the mouse brain functions in normal states. Anaesthesia is currently an integrated part of most mouse rs-fMRI experiment. However, it influences blood-oxygenation-leveldependent (BOLD) fMRI signals via modulation of neurovascular coupling and brain metabolism, and therefore alters FC and topologies of RSNs. Investigating FC and its changes associated with genes therefore initially requires an understanding of the anaesthetics. Furthermore, various anaesthetic protocols are adopted by different labs leading to difficulties in result comparisons. The brain is a complex and hierarchical system, whereby its RSN architecture can be characterised from mutiple perspectives at regional or global levels. Previous mouse rs-fMRI studies have focused on long-distance FC, however, given the non-uniform influence of anaesthesia on the brain, mapping functional activations across scales in mice under different anaesthetics remain sparsely explored. Establishing this relationahsip would provide a reliable reference to study mouse brain functions in abnormal states and facilitate comparisons across laboratories. | P a g eIn the first aim of this thesis, I investigated the local connectivity in wide type (WT) mice under six commonly used anaesthetic regimens. I identified that the regional connectivity altered across the brain as a function of the expression density of receptors relative to specific agents. In addition, the depth of anaesthesia influences local synchronization.In the seco...

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Anaesthetic modulation of synaptic transmission in the mammalian CNS

Cited by 55 publications

References 83 publications

Sevoflurane Inhibition of the Slowly Activating Delayed Rectifier K+ Current in Guinea Pig Ventricular Cells

Sevoflurane Inhibition of the Slowly Activating Delayed Rectifier K+ Current in Guinea Pig Ventricular Cells

Effect of thiopental sodium on N-methyl-D-aspartate-gated currents

Functional network study on the wild type and DISC1 transgenic mice

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