Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABAA receptor α1 subtype

  title={Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABAA receptor $\alpha$1 subtype},
  author={R M McKernan and Thomas W. Rosahl and David S. Reynolds and Cyrille Sur and K. A. Wafford and J. R. Atack and Sophie J. Farrar and Janice Myers and Gina P Cook and Pushpinder Ferris and L. Garrett and L J Bristow and George R. Marshall and Alison J. Macaulay and N A Brown and Owain Howell and Kevin W. Moore and Robert W. Carling and L Street and Jos{\'e} L. Castro and C. Ian Ragan and G. R. Dawson and P J Whiting},
  journal={Nature Neuroscience},
Inhibitory neurotransmission in the brain is largely mediated by GABAA receptors. Potentiation of GABA receptor activation through an allosteric benzodiazepine (BZ) site produces the sedative, anxiolytic, muscle relaxant, anticonvulsant and cognition-impairing effects of clinically used BZs such as diazepam. We created genetically modified mice (α1 H101R) with a diazepam-insensitive α1 subtype and a selective BZ site ligand, L-838,417, to explore GABAA receptor subtypes mediating specific… 

Are GABAA Receptors Containing α5 Subunits Contributing to the Sedative Properties of Benzodiazepine Site Agonists?

It could be of importance to avoid substantial agonist activity at α5 receptors by candidate anxioselective anxiolytics, if clinical sedation is to be avoided, as sedation may be partly dependent on activity mediated by α5-containing GABAA receptors.

Selective Antagonism of GABAA Receptor Subtypes: An In Vivo Approach to Exploring the Therapeutic and Side Effects of Benzodiazepine–Type Drugs

Results indicate that subtype-selective antagonists represent a useful approach to studying receptor mechanisms underlying the behavioral effects of BZ-type drugs.

Subtype-selective GABAA receptor mimetics—novel antihyperalgesic agents?

Evidence from genetically modified mice now indicates that agents targeting only a subset of benzodiazepine (GABAA) receptors should provide pronounced antihyperalgesic activity against inflammatory and neuropathic pain.

A new benzodiazepine pharmacology.

Rational drug targeting to specific receptor subtypes has now become possible, and only restricted neuronal networks will be modulated by the new subtype-selective drugs.

Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes

The identification of separable key functions of GABAA receptor subtypes suggests that receptor subtype-selective compounds could overcome the limitations of classical benzodiazepines; furthermore, they might be valuable for novel indications such as chronic pain, depression, schizophrenia, cognitive enhancement and stroke.

Differential Roles of GABAA Receptor Subtypes in Benzodiazepine-Induced Enhancement of Brain-Stimulation Reward

The neural mechanisms of the behavioral effects of benzodiazepines using the intracranial self-stimulation (ICSS) test implicate α2 and α3 subunit containing GABAA receptors as key mediators of the reward-related effects of Benzodiazepine.

Selective anxiolysis produced by ocinaplon, a GABA(A) receptor modulator.

  • A. LippaP. Czobor P. Skolnick
  • Psychology, Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 2005
It is reported that the pyrazolo[1,5-a]-pyrimidine, ocinaplon, exhibits an anxioselective profile in both preclinical procedures and in patients with generalized anxiety disorder, the most common of the anxiety disorders.

Development of Subtype Selective GABAA Modulators

It may be possible to develop effective anxiolytic compounds that have a much reduced side-effect profile compared with existing drugs, according to the phenotypic analysis of transgenic knock-in and knock-out mice.



Benzodiazepine actions mediated by specific γ-aminobutyric acidA receptor subtypes

GABAA (γ-aminobutyric acidA) receptors are molecular substrates for the regulation of vigilance, anxiety, muscle tension, epileptogenic activity and memory functions, which is evident from the

Cerebellar GABAA receptor selective for a behavioural alcohol antagonist

It is concluded that this α-subunit is part of a cerebellar receptor subtype, selective for Rol5-4513 (refs 17, 18), an antagonist of alcohol-induced motor incoordination and ataxia, and photoaffinity-labelled with benzodiazepines.

Type I and type II GABAA-benzodiazepine receptors produced in transfected cells.

Diversity in benzodiazepine pharmacology is generated by heterogeneity of the alpha subunit of the GABAA receptor, indicating that there are subtypes within the type II class.

γ‐Aminobutyric AcidA Receptor α5‐Subunit Creates Novel Type II Benzodiazepine Receptor Pharmacology

A cDNA encoding a protein with 70% amino acid identity to the previously characterized γ‐aminobutyric acidA (GABAA receptor α‐subunits) was isolated from a rat brain cDNA library by homology screening and a reclassification of the GABAA/benzodiazepine receptors is warranted.

Comparison of benzodiazepine (BZ) receptor agonists in two rodent activity tests

Results are consistent with the hypothesis that the chain-pulling test is sensitive to sedation induced by BZ receptor agonists, as zolpidem is a preferentially sedative compound.

GABAA‐receptor heterogeneity in the adult rat brain: Differential regional and cellular distribution of seven major subunits

This study identifies immunohistochemically the main subunit combinations expressed in the adult rat brain and allocates them to identified neurons, providing the basis for a functional analysis of GABAA‐receptor subtypes of known subunit composition and may open the way for unproved therapeutic approaches based on the development of subtype‐selective drugs.

International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function.

This article does not aim to review in detail the properties of γ-aminobutyric acidA(GABAA)breceptors, but in this same journal, a review of the binding properties and pharmacology of these receptors has been published.