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

Abstract

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 physiological effects. These two complimentary approaches revealed that the α1 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.

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Figure 1: Generation of α1H101R mice.
Figure 2: Pharmacological characterization of the GABAA receptors of α1 H101R mice.
Figure 3: Behavioral evaluation of α1H101R mice.
Figure 4: Properties of L-838,417.
Figure 5: Behavioral analysis of the properties of L-838,417.

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Acknowledgements

The authors acknowledge the continued support of F. Hefti and R. Hill. We also thank Richard Newman and G. O'Meara for assessment of animals and P. Wingrove for binding studies on recombinant α1 H101R.

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Correspondence to R. M. McKernan.

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McKernan, R., Rosahl, T., Reynolds, D. et al. Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABAA receptor α1 subtype. Nat Neurosci 3, 587–592 (2000). https://doi.org/10.1038/75761

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