GABA is the major inhibitory neurotransmitter in the mammalian brain, and as many as one-third of all synapses are GABAergic [15]. Most inhibition is mediated by GABA_A receptors, which are chloride-permeable ligand-gated ion channels. Activation of GABA_A receptors generally leads to an influx of chloride, hyperpolarization of the cell membrane, shunting of excitatory input, and reduced excitability of the neurons [11]. The GABA_A receptor itself is a heteropentameric complex composed of five different subunits, and 19 subunits (α_1-6, β_1-3, γ_1-3, δ, ε, ψ, π and ρ_1-3) have been known until now [16]. The combinations of α, β, and γ subunits are the most common with the ratio of 2 : 2 : 1. The γ subunit may be replaced by a δ or ε subunit, depending on the brain region. The subunit composition can alter the biophysical properties of the receptors and drug sensitivity [17].

GABA_A receptors clustered at postsynaptic terminals are activated by a near-saturating concentration of GABA. GABA transmits information to inhibitory synapse by generating the fast and transient inhibitory postsynaptic currents (IPSCs) (Fig. 1) [18]. For many years, enhancement of fast synaptic inhibition was widely thought to be the primary mechanism underlying the actions of many GABAergic drugs.

Over the past decade, however, a persistent form of tonic inhibition has been identified in several brain regions. Tonic currents are known to be generated as GABA acts on the GABA_A receptor at the extrasynapse, not on synapse (Fig. 1) [8,19]. This tonic inhibitory conductance is generated by high-affinity, slowly desensitizing GABA_A receptors that are activated by low ambient concentration of GABA [20-22]. Tonic currents are generated in several types of cells including CA1 pyramidal [8,23], granule cells [24], and interneurons [19,25] of the hippocampus. In the hippocampus, the tonic conductance is also activated by GABA released by action potential dependent vesicular mechanism [26]. The tonic conductance has been shown to regulate neuronal excitability and information processing [19,27].

General anesthetics enhance the action of the neurotransmitter GABA on the GABA_A receptor. They potentiate IPSCs generated by the synaptic GABA_A receptor [1,2,28]. In addition, several anesthetics have been shown to reduce desensitization of GABA_A receptors [28,29] (Fig. 2A and B). At higher concentration, anesthetics directly activate GABA_A receptors without the help of GABA [28].

The tonic currents generated by the extrasynaptic GABA_A receptors are also potentiated by general anesthetics [7,21,22]. The enhancement of inhibitory currents by general anesthetics is called charge transfer. The increase of charge transfer by tonic currents is 2-3 times larger than that by miniature inhibitory postsynaptic currents (mIPSCs) (Fig. 2C) [23]. Thus, the tonic current function of anesthesia is drawing increasing attention. The difference in pharmacological and kinetic properties by synpatic or extrasynaptic GABA_A receptors has been known to be caused by the different composition of the subunits [8]. Hence, a number of studies are performed on the various functions of general anesthetics and their relations with GABA_A subunits receptors.

Volatile anesthetics are low-potency compounds that influence a variety of receptors at clinically relevant concentrations [1]. In addition, behavioral testing with volatile anesthetics is difficult for practical reasons. Nonetheless, α₁, β₁ and β₃ subunits of the GABA_A receptor have been known as the important functional sites of volatile anesthetics [30,31]. Particularly, two amino acids in the of α₁ subunit are critical for anesthetic action: serine 270 in the transmembrane 2 region and alanine 291 near the extracellular regions of transmembrane 3 [30]. Various GABA_A subunit receptors have been recognized as being related to the inhibition of the nervous system.

The impairment of memory is one of the most potent effects of many general anesthetics. Memory is particularly sensitive to general anesthetics because amnesia occurs at concentrations well below those that cause sedation and analgesia [32]. The dose of etomidate that impairs memory is considerably lower than the dose that causes immobility [7]. In the case of isoflurane, reduced cognitive function and amnesia are caused at a concentration remarkably lower than 1 MAC [8]. GABAergic tonic currents occurring in the hippocampus are closely connected with memory, playing an important role in cognition [7,8]. Low concentration of propofol [33], etomidate [7], and isoflurane [8] enhance the tonic currents through the α₅ GABA_A receptors in the hippocampus. Although the ratio of the GABA_A receptor subunits that have α₅ is low, they are distributed at the extrasynapse of the hippocampus in a relatively high ratio [34,35]. Some researches show that α₅GABA_A subunit receptors are related to learning and memory. The mice with chromosomal depletion (α₅-/-) at the α₅GABA_A subunit receptor showed better hippocampus-dependent learning than those of the wild type [36]. The memory of mice was improved when the position 105 histidine of α₅ subunit was substituted with arginine (α₅His105Arg) [37]. Therefore, it can be assumed that general anesthetics potentiate the tonic currents acting on the α₅GABA_A receptor in the hippocampus, which can be considered as one of the amnesia mechanisms that occur during anesthesia.

Sedation refers to a decreased level of arousal, as indicated by longer response times, decreased motor activity, and slurred speech. In animal models, sedation is assessed by the levels of reduced motor activity and arousal [38]. Sedation by etomidate occurs at another isoform of the α₅GABA_A receptor related to amnesia. In β₂ subunit (β₂Asn265Ser) mice, low doses of etomidate failed to reduce spontaneous locomotor activity, which implies that the sedative actions of etomidate depend on GABA_A receptors containing the β₂ subunit [39]. Diazepam, which has distinct sedation activity, is related to the position 101 histidine of the α₁ subunit [40]. The α₁ and β₂ subunit-containing GABA_A receptors in the neocortex are thought to contribute to the sedative actions of several inhaled anesthetics [9]. Tonic current in the thalamic VB neurons may contribute to the sedative action [10].

Hypnosis typically requires higher concentrations of anesthetics than sedation and is often measured by the loss of the righting reflex in rodents [38]. Etomidate induced hypnosis also depends on the β₃ (Asn256Met) subunit, being partly related with the GABA_A receptor β₂ subunit, as well [41]. Hypnosis by anesthetics is presumed to be related with the thalamus [42] and the tuberomammillary nucleus of the hypothalamus [43], though it is yet unproved.

The glycine receptor is known as an important target of inhalation anesthetics in the spinal cord [6]. This receptor, composed of four α subunits and a single β subunit, shows the inhibitory function by enhancing the inflow of chloride ions into the cells, the same as GABA_A receptors. It has been known that the glycine receptor is particularly strong for the loss of response to a painful stimulus, which appears to be determined predominantly by actions in the spinal cord [6,44].

Nicotinic acetylcholine receptors are also involved in the control of synaptic conduction in CNS. Activation of this receptor causes excitatory postsynaptic currents (EPSCs) by the inflow of cation into the cells. It has been known that general anesthetics show the repressive function by blocking EPSCs at a low concentration [45].

Ionotropic glutamate receptors generate EPSCs by the permeation of cation as well. Inhaled anesthetics block excitatory neurotransmission by inhibiting not only postsynaptic glutamate receptors but also the glutamate release from presynapse [46,47].

Volatile anesthetics activate the two-pore-domain potassium channels, which plays an important role in forming the resting membrane potential [5,48]. Activation of this channel causes inhibition of the neuron activity and hyperpolarization by increasing the conductance of potassium ions.

The voltage-gated sodium channel plays an important role in axonal conduction, synaptic integration, and neuronal excitation [5]. General anesthetics, particularly, inhibit the presynaptic voltage-gated sodium channels in glutamatergic synapse, which inhibits the excitation of the neuron by blocking the release of presynaptic neurotransmitters [5,13].