Effects of Halothane and Propofol on Excitatory and Inhibitory Synaptic Transmission in Rat Cortical Neurons

Abstract

General anesthetics are thought to act on both excitatory and inhibitory neuronal pathways at both post-and presynaptic sites. However, the literature in these regards is somewhat controversial. The aim of the present study was to reassess the relative importance of the various anesthetic actions using a common preparation. Rat cortical neurons in primary culture were used to record spontaneous miniature postsynaptic currents by the whole-cell patch-clamp technique. Halothane at clinically relevant concentrations prolonged the decay phase of spontaneous miniature inhibitory postsynaptic currents (mIPSCs) recorded in the presence of tetrodotoxin and at higher concentrations decreased the frequency of mIPSCs. The mIPSC amplitudes underwent little change. Spontaneous action potential-dependent IPSCs recorded in the absence of tetrodotoxin were similarly affected by halothane. Halothane also decreased the frequency of spontaneous miniature non-N-methyl-D-aspartate (NMDA) excitatory postsynaptic currents (mEPSCs) as well as spontaneous action potential-dependent NMDA EPSCs and non-NMDA EPSCs without affecting their decay phase. The halothane effect on mIPSC and mEPSC frequency was dependent on the external calcium concentration. In contrast to halothane, the only effect of propofol was the prolongation of the decay phase of mIPSCs and IPSCs. The prolongation of mIPSCs and IPSCs by halothane and propofol coupled with the ineffectiveness on mEPSCs and EPSCs suggests a selective postsynaptic modulation of GABA A receptors. The additional calcium-dependent inhibition of mIPSC and mEPSC frequency by halothane (but not propofol) suggests a more general mechanism by this anesthetic on presynaptic transmitter release.

Propofol enhances both tonic and phasic inhibitory currents in second-order neurons of the solitary tract nucleus (NTS)

“…Propofol did not alter the shape of EPSC events whether evoked or spontaneous, a result consistent with cortical neurons (Kitamura et al, 2003). The latency of ST triggered events is a sensitive, integrated index of axon conduction and terminal excitation that includes voltage dependent channel function such as sodium channels (Jin et al, 2004b;Bailey et al, 2006b).…”

“…Similar response patterns for propofol actions (from 1 µM) on GABAergic miniature and/or spontaneous IPSCs occur in brainstem cardiac projection neurons (Wang et al, 2004). Propofol likewise affected GABA A IPSCs in supramedullary neurons from embryonic to early postnatal brain slices from the hippocampus (from 0.2 µM) (Bai et al, 2001), paraventricular nucleus (from 10 µM, decay time (Shirasaka et al, 2004)) and cortex (primary culture, from 1 µM (Kitamura et al, 2003)). Note that experimental design factors such as Cl − gradient and driving force influence discrimination of such threshold values particularly regarding GABA A mediated currents.…”

Effects of the anesthetic agent propofol on neural populations

“…Our approach is motivated by the experimental findings on anesthetic agents (Rundshagen et al 2004;Kuizenga et al 2001) with respect to their effect on excitatory and inhibitory synapses. For example, increasing the concentration of the agent propofol prolongs the temporal decay phase of inhibitory GABA A synapses and increases the charge transfer in these synapse (Baker et al 2002) while excitatory synapses remain more or less unaffected (Kitamura et al 2002). In addition, to a good approximation the height of the synaptic response function is maintained for different propofol concentrations (Kitamura et al 2002).…”

“…It acts mainly on GABA A receptors and hence changes the response of inhibitory synapses, while NMDAand non-NMDA excitatory receptors are insignificantly affected. Increasing the blood concentration of propofol increases the charge transfer in synaptic GABA A -receptors and increases the decay time constant of their synaptic response function (Kitamura et al 2002). We point out that the present work is not limited to the action of propofol and may be applied to the action of other anesthetic agents.…”

“…To investigate whether the latter model assumptions on the inhibitory synaptic response are valid, we consider experimental results on the synaptic response of GABA Asynapses measured in vitro in cultured cortical neurons of rats (Kitamura et al 2002). Figure 1a shows the mean values p obtained experimentally at GABA A -synapses subject to the propofol concentration c, together with the extreme values of p at the borders of the error bars.…”