The Effects of General Anesthetics on Synaptic Transmission

Abstract

General anesthetics are a class of drugs that target the central nervous system and are widely used for various medical procedures. General anesthetics produce many behavioral changes required for clinical intervention, including amnesia, hypnosis, analgesia, and immobility; while they may also induce side effects like respiration and cardiovascular depressions. Understanding the mechanism of general anesthesia is essential for the development of selective general anesthetics which can preserve wanted pharmacological actions and exclude the side effects and underlying neural toxicities. However, the exact mechanism of how general anesthetics work is still elusive. Various molecular targets have been identified as specific targets for general anesthetics. Among these molecular targets, ion channels are the most principal category, including ligand-gated ionotropic receptors like γ-aminobutyric acid, glutamate and acetylcholine receptors, voltage-gated ion channels like voltage-gated sodium channel, calcium channel and potassium channels, and some second massager coupled channels. For neural functions of the central nervous system, synaptic transmission is the main procedure for which information is transmitted between neurons through brain regions, and intact synaptic function is fundamentally important for almost all the nervous functions, including consciousness, memory, and cognition. Therefore, it is important to understand the effects of general anesthetics on synaptic transmission via modulations of specific ion channels and relevant molecular targets, which can lead to the development of safer general anesthetics with selective actions. The present review will summarize the effects of various general anesthetics on synaptic transmissions and plasticity.

Keywords: Neuropharmacology; general anesthetics; ion channels; neurotransmitter; synaptic plasticity; synaptic transmission.

Fig. (1)

Diverse structures of general anesthetics. A: Volatile anesthetics including halothane, isoflurane, sevoflurane and desflurane. The chemical name of halothane is 2-bromo-2-chloro-1,1,1-trifluoroethane, belongs to a different class of compounds than fluorinated ether for isoflurane, sevoflurane and desflurane. But they produce similar pharmacological actions including amnesia, hypnosis, unconsciousness and immobility. B: Commonly used tool drug for anesthetic research F6. F6 has similar physicochemical properties to volatile anesthetics, but F6 cannot produce general anesthetic actions including unconsciousness and immobility. These facts indicate that physicochemical property (e.g. lipid solubility) is not the determined mechanism for general anesthesia. C: Commonly used intravenous general anesthetics, including propofol, etomidate, ketamine and phenobarbital. The structures of these intravenous general anesthetics are varied while all induce unconsciousness. Nevertheless, the discrepancy in structure determined various mechanisms of general anesthesia by enhancing inhibitory neuron or inhibiting excitatory neuron, and even might be associated with other effect, such as sympathetic suppression or activation.

Fig. (2)

Physiological process of synaptic transmission and possible synaptic targets for general anesthetics. A: Main process of chemical synaptic transmission in physiological condition. Action potentials mediated by voltage-gated sodium channel propagate to terminal boutons and depolarize the presynaptic membrane. The depolarization results in calcium influx and exocytosis for neurotransmitter release by vesicles fusion with presynaptic membrane. The released neurotransmitter binds and activates postsynaptic receptors, further lead to excitatory or inhibitory postsynaptic potential. B: Underlying targets for general anesthetics on synaptic transmission. Theoretically, all the components participating the synaptic transmission are possible targets of general anesthetics. General anesthetics modulate synaptic actions by both pre- (release) and post-synaptic (receptor) mechanisms. At presynaptic part, voltage-gated sodium channel (Na_v), voltage-gated calcium channel (Ca_v) and the soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor (SNARE) are key targets of general anesthetics to inhibiting neurotransmitter release. At postsynaptic part, general anesthetics act mainly by enhancing inhibitory neuronal receptor, such as γ-aminobutyric acid (GABA) and glycine receptors, or suppressing excitatory neuronal receptors such as glutamate and acetylcholine receptors [25]. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Fig. (3)

Effects of isoflurane on GABA and glutamate release. A-B: Isoflurane inhibits calcium influx measured by fluorescence imaging of GCaMP3 (A). Calcium influx is inhibited by isoflurane in a concentration-dependent manner. The blue bar indicates the clinically relevant concentrations of isoflurane (0.175-0.7 mM) (B); C: Fluorescence imaging experiment demonstrated that isoflurane significantly depress exocytosis as measured by vGlut-pHlourin; D-E: The depression of isoflurane on exocytosis and Ca²⁺ influx is more potent for glutamate (Glut) than GABA [39]; F: The depression of isoflurane on 4AP-evoked release of glutamate and GABA are different in various part of central nervous system including cortex, hippocampus, striatum and spinal cord. The blue bar indicates the clinically relevant concentrations of isoflurane (0.175-0.7 mM) [62]. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Fig. (4)

Effects of isoflurane on voltage-gated sodium channels. A: Effects of isoflurane on voltage-gated sodium channel (Na_v) gating. Na_v typically exists in three states, resting, open and inactivated. Isoflurane can significantly stabilize inactivated state of sodium channels by facilitating voltage-dependent inactivation and delaying recovery from inactivation [79]; B: The effect of isoflurane on voltage-dependent activation of Na_v is insignificant; C: Isoflurane significantly hyperpolarized voltage-dependent inactivation curve of Na_v; D: Isoflurane significantly delay recovery of Na_v from steady-state inactivation; E-F: Voltage- and use-dependent inhibition of isoflurane on sodium peak currents. The inhibition of isoflurane on sodium peak currents is more potent from the depolarized holding potential (V_1/2inact) than physiologically relevant potential (-70 mV) [80]. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Fig. (5)

Structure of GABA_A receptors and general anesthetics binding sites. A-B: Brief structures of GABA_A receptor, which contains five subunits and four transmembrane domains for each subunit. Each subunit has a binding domain extracellularly and regulatory domain intracellularly. C: The released GABA from presynaptic membrane activates GABA_A receptors, which then leading to chloride influx and hyperpolarization of postsynaptic membrane; D: The possible binding sites for benzodiazepines (upper), propofol and etomidate (lower) on GABA_A receptor. Benzodiazepines binds GABA_A receptors at extra-membrane site between α and γ subunits. However, propofol and etomidate can bind the α and β subunits at their transmembrane domains. (A higher resolution / colour version of this figure is available in the electronic copy of the article).