Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype
by
McKernan RM, Rosahl TW, Reynolds DS, Sur C, Wafford KA,
Atack JR, Farrar S, Myers J, Cook G, Ferris P,
Garrett L, Bristow L, Marshall G, Macaulay A, Brown N,
Howell O, Moore KW, Carling RW, Street LJ,
Castro JL, Ragan CI, Dawson GR, Whiting PJ.
Neuroscience Research Centre,
Merck Sharp and Dohme Research Laboratories,
Terlings Park, Eastwick Road,
Harlow, Essex CM20 2QR, UK.
Ruth_McKernan@Merck.com
Nat Neurosci. 2000 Jun;3(6):587-92

ABSTRACT

Inhibitory neurotransmission in the brain is largely mediated by GABA(A) 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 (alpha1 H101R) with a diazepam-insensitive alpha1 subtype and a selective BZ site ligand, L-838,417, to explore GABA(A) receptor subtypes mediating specific physiological effects. These two complimentary approaches revealed that the alpha1 subtype mediated the sedative, but not the anxiolytic effects of benzodiazepines. This finding suggests ways to improve anxiolytics and to develop drugs for other neurological disorders based on their specificity for GABA(A) receptor subtypes in distinct neuronal circuits.

GABAergic drugs
Benzodiazepines
Neuroactive steroids
GABA(A) and fluoxetine
Anxiolytics and antidepressants
GABA, pain and the cerebral cortex
Anxioselective compounds and GABA(A)

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