title: Are extrasynaptic GABAA receptors important targets for sedative/hypnotic drugs?
abstract: High-affinity extrasynaptic GABA(A) receptors are persistently activated by the low ambient GABA levels that are known to be present in extracellular space. The resulting tonic conductance generates a form of shunting inhibition that is capable of altering cellular and network behavior. It has been suggested that this tonic inhibition will be enhanced by neurosteroids, antiepileptics, and sedative/hypnotic drugs. However, we show that the ability of sedative/hypnotic drugs to enhance tonic inhibition in the mouse cerebellum will critically depend on ambient GABA levels. For example, we show that the intravenous anesthetic propofol enhances tonic inhibition only when ambient GABA levels are <100 nm. More surprisingly, the actions of the sleep-promoting drug 4,5,6,7-tetrahydroisothiazolo-[5,4-c]pyridin-3-ol (THIP) are attenuated at ambient GABA levels of just 20 nm. In contrast, our data suggest that neurosteroid enhancement of tonic inhibition will be greater at high ambient GABA concentrations. We present a model that takes into account realistic estimates of ambient GABA levels and predicted extrasynaptic GABA(A) receptor numbers when considering the ability of sedative/hypnotic drugs to enhance tonic inhibition. These issues will be important when considering drug strategies designed to target extrasynaptic GABA(A) receptors in the treatment of sleep disorders and other neurological conditions.
authors.affiliation: Biophysics Section, Division of Cell and Molecular Biology, Imperial College, South Kensington, London SW7 2AZ, United Kingdom.
authors.forename: Catriona M
authors.initials: CM
authors.lastname: Houston
authors.forename: Thomas P
authors.initials: TP
authors.lastname: McGee
authors.forename: Georgina
authors.initials: G
authors.lastname: Mackenzie
authors.forename: Kevin
authors.initials: K
authors.lastname: Troyano-Cuturi
authors.forename: Pablo Mateos
authors.initials: PM
authors.lastname: Rodriguez
authors.forename: Elena
authors.initials: E
authors.lastname: Kutsarova
authors.forename: Efthymia
authors.initials: E
authors.lastname: Diamanti
authors.forename: Alastair M
authors.initials: AM
authors.lastname: Hosie
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Franks
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Brickley
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D016503:Drug Delivery Systems / Q000379:methods; D057809:HEK293 Cells; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009924:Organ Culture Techniques; D011963:Receptors, GABA-A / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D006993:Hypnotics and Sedatives; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid