Sedation and anesthesia mediated by distinct GABA(A) receptor isoforms

David S Reynolds; Thomas W Rosahl; Jennifer Cirone; Gillian F O'Meara; Alison Haythornthwaite; Richard J Newman; Janice Myers; Cyrille Sur; Owain Howell; A Richard Rutter; John Atack; Alison J Macaulay; Karen L Hadingham; Peter H Hutson; Delia Belelli; Jeremy J Lambert; Gerard R Dawson; Ruth McKernan; Paul J Whiting; Keith A Wafford

doi:10.1523/JNEUROSCI.23-24-08608.2003

Sedation and anesthesia mediated by distinct GABA(A) receptor isoforms

J Neurosci. 2003 Sep 17;23(24):8608-17. doi: 10.1523/JNEUROSCI.23-24-08608.2003.

Affiliation

¹ Merck Sharp & Dohme Research Laboratories, The Neuroscience Research Centre, Harlow, Essex CM20 2QR, United Kingdom.

Abstract

The specific mechanisms underlying general anesthesia are primarily unknown. The intravenous general anesthetic etomidate acts by potentiating GABA(A) receptors, with selectivity for beta2 and beta3 subunit-containing receptors determined by a single asparagine residue. We generated a genetically modified mouse containing an etomidate-insensitive beta2 subunit (beta2 N265S) to determine the role of beta2 and beta3 subunits in etomidate-induced anesthesia. Loss of pedal withdrawal reflex and burst suppression in the electroencephalogram were still observed in the mutant mouse, indicating that loss of consciousness can be mediated purely through beta3-containing receptors. The sedation produced by subanesthetic doses of etomidate and during recovery from anesthesia was present only in wild-type mice, indicating that the beta2 subunit mediates the sedative properties of anesthetics. These findings show that anesthesia and sedation are mediated by distinct GABA(A) receptor subtypes.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anesthetics / pharmacology*
Animals
Anticonvulsants / pharmacology
Behavior, Animal / drug effects
Binding, Competitive / drug effects
Bridged Bicyclo Compounds, Heterocyclic / pharmacokinetics
Cell Separation
Consciousness / drug effects
Dose-Response Relationship, Drug
Electroencephalography / drug effects
Etomidate / pharmacology*
Gene Targeting
Hypnotics and Sedatives / pharmacology*
In Vitro Techniques
Male
Mice
Mice, Mutant Strains
Motor Activity / drug effects
Patch-Clamp Techniques
Protein Isoforms / genetics
Protein Isoforms / metabolism
Purkinje Cells / cytology
Purkinje Cells / drug effects
Purkinje Cells / physiology
Receptors, GABA-A / drug effects
Receptors, GABA-A / genetics
Receptors, GABA-A / metabolism*
Recovery of Function / drug effects
Recovery of Function / genetics
Triazoles / pharmacology

Substances

Anesthetics
Anticonvulsants
Bridged Bicyclo Compounds, Heterocyclic
Hypnotics and Sedatives
Protein Isoforms
Receptors, GABA-A
Triazoles
loreclezole
tert-butylbicyclophosphorothionate
Etomidate