Are Extrasynaptic GABA_AReceptors 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 Ͻ100 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.

Assessment of subunit-dependent direct gating and allosteric modulatory effects of carisoprodol at GABAA receptors

“…We found that, as reported for other ligands (Bianchi and Macdonald, 2003), carisoprodol has higher efficacy at extrasynaptic α1β3δ and α4β3δ receptors than does GABA, and carisoprodol was about 90% as efficacious as the full agonist THIP. The efficacy of general anesthetics and sedative/hypnotics in potentiation of GABA-gated currents at extrasynaptic α6β2δ GABA A receptors depends upon the ambient GABA concentration or GABA occupancy of the receptors (Houston et al, 2012). The general anesthetic propofol and sleep-inducing drug THIP potentiate only when the ambient GABA levels are low and cease to modulate at saturating GABA.…”

“…The general anesthetic propofol and sleep-inducing drug THIP potentiate only when the ambient GABA levels are low and cease to modulate at saturating GABA. On the other hand, the neurosteroid THDOC (3α,21-dihydroxy-5α-pregnan-20-one) has stronger potentiating effects on saturated GABA currents compared to submaximal GABA currents (Houston et al, 2012; Wohlfarth et al, 2002). We found that carisoprodol potentiated at both sub-saturating and saturating GABA concentrations.…”

Synaptic-Type α1β2γ2L GABAA Receptors Produce Large Persistent Currents in the Presence of Ambient GABA and Anesthetic Drugs

“…Thus, potentiation of steady-state currents from a1b2g2L receptors may contribute to the sedative effect of propofol. The concentration of steady-state GABA to which the receptors are exposed under physiologic conditions is estimated at or below 0.5 mM (multiple references in Houston et al, 2012). Although exposure of a1b2g2L to 0.5 mM GABA elicited an Fig.…”

“…A recent study found that the ability of GABA A receptor potentiators to enhance tonic currents depends on ambient GABA concentration (Houston et al, 2012). This introduces yet another variable capable of affecting the final level of tonic inhibition in the presence of sedative drugs.…”

“…The conventional view is that synaptic-type receptors are minimally affected by the presence of low ambient GABA. Indeed, the concentration of extracellular GABA (Houston et al, 2012) is several tens of folds lower than the apparent affinity to GABA of synaptic subtypes of GABA A receptors (Li et al, 2006;Picton and Fisher, 2007).…”