Neocortex is the major target of sedative concentrations of volatile anaesthetics: strong depression of firing rates and increase of GABA_A receptor‐mediated inhibition

Abstract

General anaesthetics cause sedation, amnesia and hypnosis. Although these clinically desired actions are indicative of an impairment of neocortical information processing, it is widely held that they are to a large part mediated by subcortical neural networks. Anaesthetic action on brain stem, basal forebrain and thalamus, all of which are known to modulate cortical excitability, would thus ultimately converge on neocortex, perturbing and reducing action potential activity therein. However, as neocortex harbours molecular targets of anaesthetics in high densities, notably GABA(A) receptors, neocortex itself should be very sensitive to anaesthetics. Here, we performed experiments to reveal the extent to which neocortex proper is a relevant target of the low concentrations of volatile anaesthetics causing sedation and hypnosis. We compared the effects of isoflurane, enflurane and halothane on spontaneous action potential activity of rat neocortical neurons in vivo and in isolated cortical networks in vitro, i.e. in the presence and absence of subcortical arousal systems. We observed that the anaesthetics decreased spontaneous firing of neurons via intracortical mechanisms; concentrations inducing hypnosis in humans reduced discharge rates both in vivo and in vitro to the same extent, approximately 50%. This decrease in neuronal activity was paralleled by a significant enhancement of neocortical GABA(A) receptor-mediated inhibition. These findings challenge the notion of predominantly subcortical effects of volatile anaesthetics and suggest that intracortical targets, among them neocortical GABA(A) receptors, mediate the sedative and hypnotic properties of volatile anaesthetics.

Systemic administration of the benzodiazepine receptor partial inverse agonist FG‐7142 disrupts corticolimbic network interactions

“…Studies conducted in the future comparing the effects of conventional stressors and FG-7142 on the functional connectivity between mPFC and BLA will be useful to confirm the validity of using FG-7142 to model the effects of stress on corticolimbic network interactions. The effects of isoflurane, the anesthetic used in the present study, are mediated in part by potentiating cortical (Hentschke et al, 2005) and amygdaloid (Ranft et al, 2004) GABA A receptor function, the site of benzodiazepine binding and action of FG-7142 and FLU. Thus, future experiments conducted in the freely-behaving animal will avoid the potential confound of drug interactions between isoflurane, FG-7142 and/or FLU.…”

Voltage-sensitive dye imaging of transcranial magnetic stimulation-induced intracortical dynamics

“…The disappearance of the notch does not exclude additional involvement of facilitatory mechanisms acting on longer timescales (42) and changing excitation-inhibition balance in favor of LTP-like excitation. Additionally, volatile anesthesia as used here reduces spontaneous activity and increases inhibition (66). Hence, the excitatory levels found after high-frequency stimulation might be underestimated, whereas notch strength before TMS might be overestimated.…”

Sleep and general anesthesia

“…Certainly, cortical neurons are sensitive to general anesthetics, 62,63 and cortical inhibition could influence thalamic activity via the descending corticofugal pathway. 64 A study that concluded that cortical changes in the EEG preceded changes in thalamic local field potentials at loss of consciousness supports this view but, interestingly, a recent study concluded the opposite during sleep onset.…”