Anesthetics Discriminate Between Tonic and Phasic γ-Aminobutyric Acid Receptors on Hippocampal CA1 Neurons

Abstract

Background Anesthesia is produced by a depression of neuronal signaling in the central nervous system (CNS), however, the mechanism(s) of action underlying this depression remain unclear. Recent studies have indicated that anesthetics can enhance inhibition of CNS neurons by increasing current flow through tonic gamma-aminobutyric acid (GABAA) receptor gated chloride channels in their membranes. Enhanced tonic inhibition would contribute to CNS depression produced by anesthetics, but it remains to be determined to what extent anesthetic actions at these receptors contribute to CNS depression. In the present study, we compared and contrasted the involvement of tonic versus synaptic GABAA receptors in the functional depression of CNS neurons produced by isoflurane and thiopental. Methods In rat hippocampal slices, whole cell patch clamp recordings were used to study anesthetic effects on CA1 neuron intrinsic excitability, and population spike recordings were used to investigate effects on synaptically evoked discharge. These responses were chosen to test whether anesthetic effects on GABA receptors alter single neuron discharge and/or circuit level synaptic functioning. Phasic (synaptic) GABA receptors were selectively blocked using the GABAA antagonist gabazine and tonic responses were blocked using the chloride channel blocker picrotoxin. Results Clinically relevant and equi-effective concentrations of thiopental and isoflurane depressed CA1 neuron synaptically evoked discharge. This depression was partially reversed by blocking synaptic GABAA receptors with gabazine (20 μM). The thiopental-induced depression was reversed by ~ 60 %, but the isoflurane-induced depression was reversed by only ~ 20%. Blocking tonic GABAA receptors with the addition of 100 μM picrotoxin produced an additional 40 % reversal of the thiopental-induced depression, but no additional reversal was seen for isoflurane-depressed responses. In response to direct DC current injection, CA1 neuron discharge was depressed by thiopental and membrane conductance was increased. Both of these effects were reversed by picrotoxin, but not by gabazine. Isoflurane, in contrast, neither depressed current-evoked discharge, nor altered the membrane conductance of CA1 neurons. Conclusions These results indicate that general anesthetics discriminate between synaptic and tonic GABAA receptors. Effects on both phasic and tonic receptors combined to depress circuit responses produced by thiopental, whereas only effects on synaptic GABA receptors appeared to play an important role for isoflurane. Together with the other known sites of action for these 2 anesthetics, our results support a multi-site, agent-specific mechanism for anesthetic actions.

Propofol Anesthesia Is Reduced in Phospholipase C–Related Inactive Protein Type-1 Knockout Mice

“…Tonic inhibition mediated by extrasynaptic GABA A -R activity is more likely to be involved in anesthetic action than phasic inhibition mediated by synaptic activity (Akk et al, 2004;Bieda and MacIver, 2004;Belelli et al, 2009;Bieda et al, 2009;Kubo et al, 2009;Herd et al, 2014). Extrasynaptic GABA A -R activity partly depends on receptor phosphorylation by various kinases such as protein kinase A and protein kinase C (Comenencia-Ortiz et al, 2014).…”

“…Extrasynaptic GABAergic transmission is more likely to contribute to general anesthesia than synaptic transmission (Semyanov et al, 2004;Bieda and MacIver, 2004;Belelli et al, 2009;Bieda et al, 2009;Kubo et al, 2009;Herd et al, 2014) . The phosphorylation state of GABA A -R is thought to determine its localization and activity in the synaptic or extrasynaptic membrane (Terunuma et al, 2004;Abramian et al, 2010;Comenencia-Ortiz et al, 2014).…”

Enhancement of GABAergic Activity: Neuropharmacological Effects of Benzodiazepines and Therapeutic Use in Anesthesiology

“…Moreover, recent study indicates that general anesthetics discriminate between synaptic and tonic GABA A Rs (Bieda et al, 2009). Extrasynaptic GABA A Rs are activated by low concentrations of GABA and as anesthetics increase the receptor affinity (Orser et al, 1998), agonist binding and current amplitude may increase (Fig.…”

Human Subthalamic Neuron Spiking Exhibits Subtle Responses to Sedatives

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