The effects of general anaesthetics on carbachol-evoked gamma oscillations in the rat hippocampus in vitro

Abstract

The effects of general anaesthetics and temperature on carbachol-evoked gamma oscillations in the rat hippocampal brain slice preparation were investigated. The frequency of the oscillations was found to be dependent on temperature in the range 32–25 °C, with a linear reduction in frequency from 40–17 Hz over this temperature range. The volatile anaesthetics isoflurane and halothane, and the intravenous anaesthetics thiopental, propofol and R(+)-etomidate caused a reduction in the frequency of the oscillations, in a concentration-dependent manner, over a range of clinically relevant concentrations. On the other hand, the intravenous agent ketamine and the “inactive” S(−)-isomer of etomidate had no significant effect on the oscillation frequency. The oscillations were markedly asymmetric over one cycle with a relatively rapid “rising” phase followed by a slower “decaying” phase. The decrease in oscillation frequency was due to an increase in the time-course of the “decaying phase” of the oscillation with little effect on the “rising” phase, consistent with the idea that carbachol-evoked gamma oscillations are trains of GABAergic inhibitory postsynaptic potentials and that the anaesthetics are acting postsynaptically at the GABA_A receptor.

Introduction

Gamma or “40 Hz” oscillations have been associated with active brain states, such as selective visual attention (Fries et al., 2001), auditory memory tasks (Lutzenberger et al., 2002) and dreaming during REM sleep (Llinas and Ribary, 1993). In contrast, during anaesthesia and deep (“slow wave”) sleep, gamma oscillations are either not observed or are much reduced (Bragin et al., 1995, Steriade et al., 1996). With in vitro brain-slice preparations, gamma oscillations can be elicited either pharmacologically or by tetanic stimulation and are either transient or persistent. Robust, persistent gamma oscillations in hippocampal brain slices can be evoked in the presence of the cholinergic agonist carbachol (Fisahn et al., 1998, Stenkamp et al., 2001). These carbachol-evoked hippocampal gamma oscillations are an emergent property of a complex neuronal network involving both excitatory (glutamatergic) and inhibitory (GABAergic) synaptic transmission (Fisahn et al., 1998, Traub et al., 2000). Despite the complexity of the underlying neuronal substrate, progress has been made in determining important characteristics of carbachol-induced gamma oscillations. While it is clear that the oscillations are under the influence of a number of factors (such as the tonic drive induced by carbachol and the kinetics of AMPA-receptor mediated excitatory post-synaptic potentials), it is generally agreed that GABAergic inhibitory post-synaptic potentials (IPSPs) are involved in the timing of the oscillations (Buhl et al., 1998, Fisahn et al., 1998), and it has been reported that the barbiturate pentobarbital reduces the oscillation frequency (Fisahn et al., 1998). The GABA_A receptor is widely believed to be a likely target for a variety of general anaesthetics (Tanelian et al., 1993, Franks and Lieb, 1994) and many anaesthetic agents have been shown to potentiate responses to exogenously applied GABA at this receptor. Surprisingly, there have been relatively few studies looking at the effects of anaesthetics on GABAergic IPSPs and we chose to use carbachol-evoked hippocampal gamma oscillations to investigate the effects of anaesthetics on GABA receptors acting within an intrinsic neuronal network.