Effects of intravenous anaesthetic agents on fast inhibitory oscillations in the rat hippocampus in vitro (original) (raw)
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British Journal of Anaesthesia
Background: General anaesthetics have marked effects on synaptic transmission, but their neuronal and circuit-level effects remain unclear. The volatile anaesthetic isoflurane differentially inhibits synaptic vesicle exocytosis in specific neuronal subtypes, but whether other common anaesthetics also have neurone-subtype-specific actions is unknown. Methods: We used the genetically encoded fluorescent Ca 2þ sensor GCaMP6f to compare the pharmacological effects of isoflurane, sevoflurane, propofol, and ketamine on presynaptic excitability in hippocampal glutamatergic neurones and in hippocampal parvalbumin-, somatostatin-, and vasoactive intestinal peptide-expressing (PV þ , SST þ , and VIP þ , respectively) GABAergic interneurones. Results: Isoflurane and sevoflurane depressed activity-driven presynaptic Ca 2þ transients in a neurone-type-specific manner, with greater potency for inhibition of glutamate and SST þ compared with PV þ and VIP þ neurone presynaptic activation. In contrast, clinical concentrations of propofol (1 mM) or ketamine (15 mM) had no significant effects on presynaptic activation. Propofol potentiated evoked Ca 2þ entry in PV þ interneurones but only at a supraclinical concentration (3 mM). Conclusions: Anaesthetic-agent-selective effects on presynaptic Ca 2þ entry have functional implications for hippocampal circuit function during i.v. or volatile anaesthetic-mediated anaesthesia. Hippocampal interneurones have distinct subtype-specific sensitivities to volatile anaesthetic actions on presynaptic Ca 2þ , which are similar between isoflurane and sevoflurane.
British Journal of Anaesthesia, 2012
† The thalamus is involved in anaesthesia. † In this study, propofol anaesthesia in rats was antagonized by physostigmine. † Increased thalamic activity was seen when physostigmine was given during propofol anaesthesia. † Impaired thalamic function is associated with anaesthesia-induced unconsciousness. Background. Positron emission tomography studies in human subjects show that propofolinduced unconsciousness in humans is associated with a reduction in thalamic blood flow, suggesting that anaesthesia is associated with impairment of thalamic function. A recent study showed that antagonism of propofol-induced unconsciousness by the anticholinesterase physostigmine is associated with a marked increase in thalamic blood flow, supporting the implication of the thalamus. The aim of the present study was to assess the role of the thalamus in the antagonistic effects of physostigmine during propofol anaesthesia using electrophysiological recordings in a rat model. Methods. Local field potentials were recorded from the barrel cortex and ventroposteromedial thalamic nucleus in 10 chronically instrumented rats to measure spectral power in the gamma/high-gamma range (50-200 Hz). Propofol was given i.v. by target-controlled infusion at the lowest concentration required to abolish righting attempts. Physostigmine was given during anaesthesia to produce behavioural arousal without changing anaesthetic concentration. Results. Compared with baseline, gamma/high-gamma power during anaesthesia was reduced by 31% in the cortex (P¼0.006) and by 65% in the thalamus (P¼0.006). Physostigmine given during anaesthesia increased gamma/high-gamma power in the thalamus by 60% (P¼0.048) and caused behavioural arousal that correlated (P¼0.0087) with the increase in power. Physostigmine caused no significant power change in the cortex. Conclusions. We conclude that partial antagonism of propofol anaesthesia by physostigmine is associated with an increase in thalamic activity reflected in gamma/ high-gamma (50-200 Hz) power. These findings are consistent with the view that anaesthetic-induced unconsciousness is associated with impairment of thalamic function.
Anesthesiology, 1999
Background In cultured slice preparations of rat neocortical tissue, clinically relevant concentrations of volatile anesthetics mainly decreased action potential firing of neurons by enhancing gamma-aminobutyric acid (GABA(A)) receptor-mediated synaptic inhibition. The author's aim was to determine if other anesthetic agents are similarly effective in this model system and act via the same molecular mechanism. Methods The actions of various general anesthetics on the firing patterns of neocortical neurons were investigated by extracellular single-unit recordings. Results Pentobarbital, propofol, ketamine, and ethanol inhibited spontaneous action potential firing in a concentration-dependent manner. The estimated median effective concentration (EC50) values were close to or below the EC50 values for general anesthesia. Bath application of the GABA(A) antagonist bicuculline (100 microM) decreased the effectiveness of propofol, ethanol, halothane, isoflurane, enflurane, and diazepa...
Journal of Neurophysiology, 2002
The effect of anesthetic drugs at central synapses can be described quantitatively by developing kinetic models of ligand-gated ion channels. Experiments have shown that the hypnotic propofol and the sedative benzodiazepine midazolam have similar effects on single inhibitory postsynaptic potentials (IPSPs) but very different effects on slow desensitization that are not revealed by examining single responses. Synchronous oscillatory activity in networks of interneurons connected by inhibitory synapses has been implicated in many hippocampal functions, and differences in the kinetics of the GABAergic response observed with anesthetics can affect this activity. Thus we have examined the effect of propofol and midazolam-enhanced IPSPs using mathematical models of self-inhibited one- and two-cell inhibitory networks. A detailed kinetic model of the GABAA channel incorporating receptor desensitization is used at synapses in our models. The most dramatic effect of propofol is the modulatio...
BJA: British Journal of Anaesthesia, 1988
General anaesthetics can depress synaptic transmission and neuronal excitability in the central nervous system (CNS) [1,2]. Although it is possible that CNS depression is the major action underlying anaesthesia, evidence exists for anaesthetic-induced facilitation of excitatory transmission [3-5] and various patterns of " activated " EEG recordings have been observed during anaesthesia [6,7]. Furthermore, anaesthetics produce agent-specific effects on CNS electrical activity in vivo [8], and a single anaesthetic state, or common neurophysiological mechanism, has not been observed for all anaesthetics. Concentration-dependent and anaesthetic-specific differential effects have also been reported on a number of invertebrate and isolated mammalian peripheral nervous system preparations [9]. These differential actions do not support a traditional "unitary" theory of anaesthesia [2,8-11]; rather, actions at multiple and selective membrane sites appear likely [12-14]. Recent studies of anaesthetic actions on vertebrate CNS neurones in vitro have not revealed differences in action between agents. For example, it was reported that a number of general anaesthetics (including inhalation agents and barbiturates) hyperpolarize neurones of the spinal cord and hippocampus [1], and a good correlation
British Journal of Pharmacology, 1999
Anaesthetic agents produce disruption in cognitive function typi®ed by reductions in sensory perception and memory formation. Oscillations within the EEG gamma and beta bands have been linked to sensory perception and memory and have been shown to be modi®ed by anaesthetic agents. 2 Synchronous gamma oscillations generated by brief tetanic stimulation in two regions of hippocampal area CA1 in slices in vitro were seen to potentiate excitatory synaptic communication between the areas. This synaptic potentiation, was seen to contribute to a transition from gamma frequency (30 ± 70 Hz) to beta frequency (12 ± 30 Hz) oscillations. 3 Four drugs having anaesthetic/hypnotic and amnesic properties were tested on this synchronous gamma-induced beta oscillation. Thiopental 10 ± 200 mM, Diazepam 0.05 ± 1.0 mM, Morphine 10 ± 200 mM, and Ketamine 10 ± 200 mM were all added to the bathing medium. Each drug markedly disrupted the formation of beta oscillations in a manner consistent with their primary modes of action. Thiopental and morphine disrupted synchrony of gamma oscillations and prevented potentiation of recurrent excitatory potentials measured in stratum oriens (fEPSPs). Neither diazepam, nor ketamine produced such marked changes in synchrony at gamma frequencies or reduction in potentiation of fEPSPs. However, each disrupted expression of subsequent beta oscillation via changes in the magnitude of inhibitory network gamma oscillations and the duration and magnitude of tetanus-induced depolarization respectively. 4 The degree of disruption of fEPSP potentiation correlated quantitatively with the degree of disruption in synchrony between sites during gamma oscillations. The data indicate that synchronous gamma-induced beta oscillations represent a mode of expression of excitatory synaptic potentiation in the hippocampus, and that anaesthetic/amnesic agents can disrupt this process markedly.
Anaesthetic modulation of synaptic transmission in the mammalian CNS
Although they affect many different organ systems within the body, general anaesthetics are administered primarily to render patients unconscious during surgical procedures. While unconscious, patients do not experience pain and the events surrounding the surgery are largely forgotten. As the brain and spinal cord are the organs that give rise to our individual and personal perceptions of the world, they are clearly the sites at which general anaesthetics exert their chief actions. Immobility, the other desirable characteristic of anaesthesia, is nowadays usually achieved by the use of muscle relaxants, which block neuromuscular transmission. It is an unfortunate fact that, whereas the pathways that are responsible for many important re¯exes are now relatively well understood, those that are involved in the emergent properties of central nervous system (CNS) function (i.e. consciousness and perception) are much less well de®ned. Although spinal pathways are involved both in re¯ex behaviour (such as limb¯exion in response to a nociceptive stimulus) and in the transmission of information about the state of the body to the brain, it is the brain that is responsible for the formation of perceptions about the world and the setting down of memory. Therefore, to understand fully how general anaesthetics work, it will be necessary to understand the neural mechanisms that underlie consciousness. This is a dif®cult problem and it may appear from this analysis that any attempt to elucidate the mechanisms involved in general anaesthesia is unlikely to succeed. However, as with many troublesome issues, a reductionist approach provides a useful starting point.
Anesthesiology, 2007
Dynamic action of anesthetic agents was compared at cortical and subcortical levels during induction of anesthesia. Unconsciousness involved the cortical brain but suppression of movement in response to noxious stimuli was mediated through subcortical structures. Twenty-five patients with Parkinson disease, previously implanted with a deep-brain stimulation electrode, were enrolled during the implantation of the definitive pulse generator. During induction of anesthesia with propofol (n = 13) or sevoflurane (n = 12) alone, cortical (EEG) and subcortical (ESCoG) electrogenesis were obtained, respectively, from a frontal montage (F3-C3) and through the deep-brain electrode (p0-p3). In EEG and ESCoG spectral analysis, spectral edge (90%) frequency, median power frequency, and nonlinear analysis dimensional activation calculations were determined. Sevoflurane and propofol decreased EEG and ESCoG activity in a dose-related fashion. EEG values decreased dramatically at loss of consciousness, whereas there was little change in ESCoG values. Quantitative parameters derived from EEG but not from ESCoG were able to predict consciousness versus unconsciousness. Conversely, quantitative parameters derived from ESCoG but not from EEG were able to predict movement in response to laryngoscopy. These data suggest that in humans, unconsciousness mainly involves the cortical brain, but that suppression of movement in response to noxious stimuli is mediated through the effect of anesthetic agents on subcortical structures.