RT Journal Article SR Electronic T1 Are Extrasynaptic GABAA Receptors Important Targets for Sedative/Hypnotic Drugs? JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 3887 OP 3897 DO 10.1523/JNEUROSCI.5406-11.2012 VO 32 IS 11 A1 Catriona M. Houston A1 Thomas P. McGee A1 Georgina MacKenzie A1 Kevin Troyano-Cuturi A1 Pablo Mateos Rodriguez A1 Elena Kutsarova A1 Efthymia Diamanti A1 Alastair M. Hosie A1 Nicholas P. Franks A1 Stephen G. Brickley YR 2012 UL http://www.jneurosci.org/content/32/11/3887.abstract AB High-affinity extrasynaptic GABAA 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 GABAA 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 GABAA receptors in the treatment of sleep disorders and other neurological conditions.