Differential contribution of GABA(A) receptor subtypes to the anticonvulsant efficacy of benzodiazepine site ligands.

Non-selective benzodiazepines, such as diazepam, interact with equivalent affinity and agonist efficacy at GABA(A) receptors containing either an alpha1, alpha2, alpha3 or alpha5 subunit. However, which of these particular subtypes are responsible for the anticonvulsant effects of diazepam remains uncertain. In the present study, we examined the ability of diazepam to reduce pentylenetetrazoLe (PTZ)-induced and maximal electroshock (MES)-induced seizures in mice containing point mutations in single (alpha1H101R, alpha2H101R or alpha5H105R) or multiple (alpha125H-->R) alpha subunits that render the resulting GABA(A) receptors diazepam-insensitive.

STOP knockout and NMDA NR1 hypomorphic mice exhibit deficits in sensorimotor gating.

Schizophrenia is a chronic and debilitating disease which is thought to arise from a neuro-developmental disorder. Both the stable tubule-only polypeptide (STOP) protein and the N-methyl-D-aspartate (NMDA) NR1 subunit are involved in neuronal development and physiology. It has therefore been postulated that transgenic mice lacking either the STOP or the NMDAR1 gene would show a 'schizophrenic-like' phenotype.

The GABA-A beta3 subunit mediates anaesthesia induced by etomidate.

The i.v. agent etomidate exerts its anaesthetic actions through potentiation of gamma-aminobutyric acid-A receptors containing beta2 and beta3 subunits.

Gamma-aminobutyric acid type A receptor beta 2 subunit mediates the hypothermic effect of etomidate in mice.

Background: The authors have previously described that the gamma-aminobutyric acid type A (GABAA) receptor beta 2N265S mutation results in a knock-in mouse with reduced sensitivity to etomidate. After recovery from etomidate anesthesia, these mice have improved motor performance and less slow wave sleep. Because most clinically used anesthetics produce hypothermia, the effect of this mutation on core body temperature was investigated.

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

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.