Volatile anesthetics and glutamate activation of N-methyl-D-aspartate receptors

Dan C Martin, Marc Plagenhoef, James Abraham, Robert L. Dennison, Robert S. Aronstam

Research output: Contribution to journalArticle

81 Citations (Scopus)

Abstract

Several studies have indicated important functional interactions between volatile anesthetics and the N-methyl-D-aspartate (NMDA) class of glutamate receptors. In the present study, we examined the effects of diethyl ether, chloroform, methoxyflurane, halothane, enflurane, and isoflurane on (1) glutamate activation of the NMDA receptor complex, including glycine reversal of anesthetic action, as revealed by [3H] (5R,10S)-(+)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine, dizocilpine (MK-801) binding to the cation channel, and (2) [3H]cis-4-(phosphonomethyl)piperidine-2-carboxylic acid (CGS 19755) binding to the glutamate recognition site of the NMDA receptor. In agreement with previous studies, glutamate increased the binding of 1 nM [3H]MK-801, measured after a 1-hr incubation at 37 °, by up to several hundred fold. This stimulation was blocked by glutamate antagonists and potentiated by glycine with an ec50 of ≈ 0.03 μM. Glycine also had a direct stimulatory effect on [3H]MK-801 binding at much higher concentrations (≥10 μM). All of the anesthetics examined depressed glutamate stimulation of [3H]MK-801 binding in a concentration-dependent manner with the following order of potency: halothane ≥ enflurane >methoxyflurane>chloroform>diethyl ether. This inhibition of [3H]MK-801 binding was observed at concentrations that are routinely attained in the cerebrospinal fluid during surgical anesthesia. Moreover, the inhibition was reversed rapidly following removal of the anesthetics from the assay medium. Inclusion of glycine in the incubation medium markedly attenuated anesthetic-induced inhibition of glutamate-sensitive [3H]MK-801 binding with an ec50 of between 0.1 and 1 μM. Thus, this reversal by glycine correlated with its potentiating, as opposed to its direct stimulatory, effect on NMDA receptors. Anesthetic inhibition of [3H]MK-801 binding could not be overcome by raising the glutamate concentration (i.e. the interaction did not appear to be competitive with respect to glutamate) unless glycine was present. Binding of [3H]CGS 19755 to the glutamate recognition site was also inhibited by each of the anesthetics examined. However, with the exception of chloroform, all of the anesthetics were more potent inhibitors of glutamate-stimulated [3H]MK-801 binding than they were of [3H]CGS 19755 binding. [3H]CGS 19755 binding saturation curves in the presence of halothane and enflurane indicated a decrease in the density of [3H]-CGS 19755 binding sites with no change in binding affinity (i.e. the inhibition did not appear to be competitive). These findings support the idea that anesthetic drugs disrupt NMDA receptor transmission through multiple allosteric effects on the receptor-channel activation mechanism and the glutamate binding site.

Original languageEnglish (US)
Pages (from-to)809-817
Number of pages9
JournalBiochemical Pharmacology
Volume49
Issue number6
DOIs
StatePublished - Mar 15 1995

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selfotel
Dizocilpine Maleate
N-Methyl-D-Aspartate Receptors
Anesthetics
Glutamic Acid
Chemical activation
Glycine
Enflurane
Halothane
Chloroform
Methoxyflurane
Ether
Binding Sites
Cerebrospinal fluid
Excitatory Amino Acid Antagonists
Imines
Isoflurane
Glutamate Receptors
N-Methylaspartate
Carboxylic Acids

Keywords

  • N-methyl-D-aspartate receptors
  • anesthetics
  • excitatory amino acid receptors
  • glutamate
  • glycine
  • halothane

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

Cite this

Volatile anesthetics and glutamate activation of N-methyl-D-aspartate receptors. / Martin, Dan C; Plagenhoef, Marc; Abraham, James; Dennison, Robert L.; Aronstam, Robert S.

In: Biochemical Pharmacology, Vol. 49, No. 6, 15.03.1995, p. 809-817.

Research output: Contribution to journalArticle

Martin, Dan C ; Plagenhoef, Marc ; Abraham, James ; Dennison, Robert L. ; Aronstam, Robert S. / Volatile anesthetics and glutamate activation of N-methyl-D-aspartate receptors. In: Biochemical Pharmacology. 1995 ; Vol. 49, No. 6. pp. 809-817.
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N2 - Several studies have indicated important functional interactions between volatile anesthetics and the N-methyl-D-aspartate (NMDA) class of glutamate receptors. In the present study, we examined the effects of diethyl ether, chloroform, methoxyflurane, halothane, enflurane, and isoflurane on (1) glutamate activation of the NMDA receptor complex, including glycine reversal of anesthetic action, as revealed by [3H] (5R,10S)-(+)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine, dizocilpine (MK-801) binding to the cation channel, and (2) [3H]cis-4-(phosphonomethyl)piperidine-2-carboxylic acid (CGS 19755) binding to the glutamate recognition site of the NMDA receptor. In agreement with previous studies, glutamate increased the binding of 1 nM [3H]MK-801, measured after a 1-hr incubation at 37 °, by up to several hundred fold. This stimulation was blocked by glutamate antagonists and potentiated by glycine with an ec50 of ≈ 0.03 μM. Glycine also had a direct stimulatory effect on [3H]MK-801 binding at much higher concentrations (≥10 μM). All of the anesthetics examined depressed glutamate stimulation of [3H]MK-801 binding in a concentration-dependent manner with the following order of potency: halothane ≥ enflurane >methoxyflurane>chloroform>diethyl ether. This inhibition of [3H]MK-801 binding was observed at concentrations that are routinely attained in the cerebrospinal fluid during surgical anesthesia. Moreover, the inhibition was reversed rapidly following removal of the anesthetics from the assay medium. Inclusion of glycine in the incubation medium markedly attenuated anesthetic-induced inhibition of glutamate-sensitive [3H]MK-801 binding with an ec50 of between 0.1 and 1 μM. Thus, this reversal by glycine correlated with its potentiating, as opposed to its direct stimulatory, effect on NMDA receptors. Anesthetic inhibition of [3H]MK-801 binding could not be overcome by raising the glutamate concentration (i.e. the interaction did not appear to be competitive with respect to glutamate) unless glycine was present. Binding of [3H]CGS 19755 to the glutamate recognition site was also inhibited by each of the anesthetics examined. However, with the exception of chloroform, all of the anesthetics were more potent inhibitors of glutamate-stimulated [3H]MK-801 binding than they were of [3H]CGS 19755 binding. [3H]CGS 19755 binding saturation curves in the presence of halothane and enflurane indicated a decrease in the density of [3H]-CGS 19755 binding sites with no change in binding affinity (i.e. the inhibition did not appear to be competitive). These findings support the idea that anesthetic drugs disrupt NMDA receptor transmission through multiple allosteric effects on the receptor-channel activation mechanism and the glutamate binding site.

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