Nature neuroscience · 2000
Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype.
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McKernan R M, Rosahl T W, Reynolds D S, Sur C, Wafford K A, Atack J R, Farrar S, Myers J, Cook G, Ferris P, Garrett L, Bristow L, Marshall G, Macaulay A, Brown N, Howell O, Moore K W, Carling R W, Street L J, Castro J L, Ragan C I, Dawson G R, Whiting P J
Аннотация
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.
Предметные рубрики MeSH
Allosteric SiteAnimalsAnti-Anxiety AgentsAnticonvulsantsAzidesBenzodiazepinesBinding, CompetitiveBrainCell LineDiazepamDose-Response Relationship, DrugFlumazenilFluorobenzenesGABA-A Receptor AntagonistsHypnotics and SedativesLigandsMiceMice, Inbred C57BLMice, Mutant StrainsMotor ActivityPatch-Clamp TechniquesReceptors, GABA-AReflex, StartleTriazoles