Background: The gamma-aminobutyric acid type A (GABA(A)) and N-methyl-d-aspartate (NMDA) receptors are important inhibitory and excitatory neurotransmitter receptors, respectively, in the central nervous system. At the concentrations required to produce immobility in the face of a noxious stimulus, volatile aromatic anesthetics inhibit NMDA receptors to varying degrees, strongly suggesting that they also act at other targets to produce immobilization. In this study, we sought to assess the potential role that GABA(A) receptors play in mediating the behavioral actions of volatile aromatic anesthetics.
Methods: Electrophysiological techniques were used to quantify the effects of eight volatile aromatic anesthetics and three clinical anesthetics on currents mediated by alpha1beta2gamma2L GABA(A) receptors expressed in Xenopus oocytes.
Results: At equivalent minimal alveolar anesthetic concentration multiples, volatile aromatic anesthetics vary widely in the degrees to which they enhance GABA(A) receptor-mediated currents elicited by low concentrations of GABA. In general, anesthetics that inhibit NMDA receptors most, enhanced GABA(A) receptors least. This reciprocal relationship between anesthetic potency on GABA(A) versus NMDA receptors was also observed for the clinical anesthetics isoflurane, halothane, and cyclopropane. Studies using a range of GABA concentrations indicated that volatile aromatic anesthetics enhance GABA(A) receptor activity by shifting the open-close (gating) equilibrium towards the open channel state.
Conclusions: These findings suggest that GABA(A) receptors contribute variably to the behavioral actions of volatile anesthetics and imply that the molecular determinants of anesthetic action on NMDA and GABA(A) receptors are distinctly different.