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Diazepam is widely prescribed as an anxiolytic but its therapeutic application is limited because with daily use tolerance develops to certain aspects of its pharmacological profile. We compared the effects of two dosing paradigms on GABA(A) receptor gene expression and benzodiazepine binding characteristics. Equivalent daily doses of 15 mg/kg/day diazepam(More)
The GABAA receptor is allosterically modulated by a number of anesthetics and barbiturates. We have examined the effects of propofol and pentobarbital on the binding of the receptor agonist [3H]muscimol and the benzodiazepine modulators [3H]flunitrazepam and [3H]Ro15-4513 to bovine brain membranes. Both agents potentiated the binding of [3H]muscimol (5 nM),(More)
Fluoxetine has been reported to be a novel allosteric modulator of GABA(A) receptors with the notable exception of receptors that contain the alpha5-subunit isoform [Robinson, R.T., Drafts, B.C., Fisher, J.L., 2003. Fluoxetine increases GABA(A) receptor activity through a novel modulatory site. J. Pharmacol. Exp. Ther. 304, 978-984]. A mutagenic strategy(More)
We investigated the recognition properties of different GABA(A) receptor subtypes and mutant receptors for the biflavonoid amentoflavone, a constituent of St. John's Wort. Radioligand binding studies showed that amentoflavone recognition paralleled that of the classical benzodiazepine diazepam in that it had little or no affinity for alpha4- or(More)
His101 of the GABA(A) receptor alpha1 subunit is an important determinant of benzodiazepine recognition and a major site of photolabeling by [3H]flunitrazepam. To investigate further the chemical specificity of the residue in this position, we substituted it with phenylalanine, tyrosine, lysine, glutamate, glutamine, or cysteine. The mutant alpha subunits(More)
The Torpedo nicotinic acetylcholine receptor is a heteropentamer (alpha2betagammadelta) in which structurally homologous subunits assemble to form a central ion pore. Viewed from the synaptic cleft, the likely arrangement of these subunits is alpha-gamma-alpha-delta-beta lying in an anticlockwise orientation. High affinity binding sites for agonists and(More)
This paper defends the claim that, in order to have a concept of time, subjects must have memories of particular events they once witnessed. Some patients with severe amnesia arguably still have a concept of time. Two possible explanations of their grasp of this concept are discussed. They take as their respective starting points abilities preserved in the(More)
We have mutated several amino acids in the region of the GABA(A) receptor alpha1 subunit predicted to form a small extracellular loop between transmembrane domains two and three to investigate its possible role in ligand sensitivity. The mutations were S275T, L276A, P277A, V279A, A280S and Y281F. Mutant alpha1 subunits were co-expressed with beta2 and(More)
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