Nature Neuroscience 3 (6): 587 - 592 (2000)
Sedative but not anxiolytic
properties of benzodiazepines
are mediated by the GABAA
receptor 1 subtype
R. M. McKernan1, T. W. Rosahl1, 2, D. S.
Reynolds1, 2, C. Sur1, 2, K. A. Wafford1, J.
R. Atack1, S. Farrar1, J. Myers1, G. Cook1,
P. Ferris1, L. Garrett1, L. Bristow1, G.
Marshall1, A. Macaulay1, N. Brown1, O.
Howell1, K. W. Moore1, R. W. Carling1, L.
J. Street1, J. L. Castro1, C. I. Ragan1, G. R.
Dawson1 & P. J. Whiting1
1. Neuroscience Research Centre, Merck Sharp and
Dohme Research Laboratories, Terlings Park, Eastwick
Road, Harlow, Essex CM20 2QR, UK
2. T.W.R., D.S.R. and C.S. contributed equally to
different aspects of this work.
Correspondence should be addressed to R M
McKernan. e-mail: Ruth_McKernan@Merck.com
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 (1 H101R) with a diazepam-insensitive 1
subtype and a selective BZ site ligand, L-838,417,
to explore GABAA receptor subtypes mediating
specific physiological effects. These two
complimentary approaches revealed that the 1
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 GABAA receptor
subtypes in distinct neuronal circuits. |
