Volatile anesthetics depress glutamate transmission via presynaptic actions

Anesthesiology. 1996 Oct;85(4):823-34. doi: 10.1097/00000542-199610000-00018.


Background: Recent evidence for a presynaptic depression of glutamate release produced by volatile anesthetics prompted the current study of isoflurane and halothane effects on glutamate-mediated transmission in the mammalian central nervous system.

Methods: Electrophysiologic recordings from CA1 neurons in rat hippocampal brain slices were used to measure anesthetic effects on glutamate-mediated excitatory postsynaptic potential (EPSP) amplitudes and paired pulse facilitation. Paired pulse facilitation is known to be altered when the calcium-dependent release of glutamate is depressed, but not when EPSP amplitudes are depressed by postsynaptic mechanisms.

Results: Isoflurane depressed EPSP amplitudes over a concentration range of 0.35-2.8 vol %, with a 50% depression (EC50) occurring at 1.0 vol % (0.71 rat minimum alveolar concentration). This depression was accompanied by an increase in paired-pulse facilitation of approximately 30% at 1.7 vol %, using interpulse intervals of 120 ms. Halothane depressed EPSP amplitudes in a concentration-dependent manner (0.3-2.4 vol %, EC50 = 1.1 minimum alveolar concentration; 1.3 vol %) and also increased facilitation by approximately 20% at 1.2 vol %. These effects persisted in the presence of 10 microM bicuculline, indicating that enhanced gamma-aminobutyric acid-mediated inhibition was not involved. The anesthetic-induced increase in facilitation and EPSP depression was mimicked by lowering extracellular calcium, which is known to depress glutamate release at these synapses. The postsynaptic glutamate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione depressed EPSP amplitudes with no change in facilitation.

Conclusions: Our results confirm earlier findings that clinically relevant concentrations of volatile anesthetics depress glutamate-mediated synaptic transmission. The observed increases in synaptic facilitation support recent findings from biochemical and electrophysiologic studies indicating presynaptic sites of action contribute to anesthetic-induced depression of excitatory transmission. This anesthetic-induced reduction in glutamate release would contribute to the central nervous system depression associated with anesthesia by adding to postsynaptic depressant actions on glutamate receptors.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Anesthetics, Inhalation / pharmacology*
  • Animals
  • Calcium / metabolism
  • Depression, Chemical
  • Electrophysiology
  • Glutamic Acid / physiology*
  • Halothane / pharmacology*
  • Hippocampus / drug effects
  • Hippocampus / physiology
  • In Vitro Techniques
  • Ion Transport
  • Isoflurane / pharmacology*
  • Male
  • Presynaptic Terminals / drug effects*
  • Presynaptic Terminals / physiology*
  • Rats
  • Rats, Sprague-Dawley
  • Synaptic Transmission / drug effects*
  • Synaptic Transmission / physiology*
  • Temperature
  • gamma-Aminobutyric Acid / physiology


  • Anesthetics, Inhalation
  • Glutamic Acid
  • gamma-Aminobutyric Acid
  • Isoflurane
  • Calcium
  • Halothane