Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype.

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

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.

Afiliación

McKernan RM; Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK. Ruth_McKernan@Merck.com

Nat Neurosci ; 3(6): 587-92, 2000 Jun.

Article en En | MEDLINE | ID: mdl-10816315

RESUMEN

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.

Asunto(s)

Ansiolíticos/farmacología; Benzodiazepinas/farmacología; Hipnóticos y Sedantes/farmacología; Receptores de GABA-A/metabolismo; Sitio Alostérico/efectos de los fármacos; Animales; Anticonvulsivantes/farmacología; Azidas/farmacocinética; Benzodiazepinas/agonistas; Benzodiazepinas/antagonistas & inhibidores; Benzodiazepinas/farmacocinética; Unión Competitiva/efectos de los fármacos; Encéfalo/efectos de los fármacos; Encéfalo/metabolismo; Línea Celular; Diazepam/farmacología; Relación Dosis-Respuesta a Droga; Flumazenil/farmacocinética; Fluorobencenos/farmacología; Antagonistas de Receptores de GABA-A; Ligandos; Ratones; Ratones Endogámicos C57BL; Ratones Mutantes; Actividad Motora/efectos de los fármacos; Técnicas de Placa-Clamp; Reflejo de Sobresalto/efectos de los fármacos; Triazoles/farmacología

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Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ansiolíticos / Benzodiazepinas / Receptores de GABA-A / Hipnóticos y Sedantes Límite: Animals Idioma: En Revista: Nat Neurosci Asunto de la revista: NEUROLOGIA Año: 2000 Tipo del documento: Article Pais de publicación: Estados Unidos

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