Enhanced Thalamic Spillover Inhibition during Non-rapid-eye-movement Sleep Triggers an Electrocortical Signature of Anesthetic Hypnosis.

BACKGROUND: Alterations in thalamic γ-aminobutyric acid-mediated signaling are thought to underlie the increased frontal α-β frequency electrocortical activity that signals anesthetic-induced loss of consciousness with γ-aminobutyric acid receptor type A (GABAAR)-targeting general anesthetics. The general anesthetic etomidate elicits phasic extrasynaptic GABAAR activation ("spillover" inhibition) at thalamocortical neurons in vitro. We hypothesize that this action of etomidate at the thalamus is sufficient to trigger an increase in frontal α-β frequency electrocortical activity and that this effect of etomidate is fully recapitulated by enhanced thalamic spillover inhibition in vivo.

METHODS: We recorded electrocortical activity and sleep-wake behavior in freely behaving wild-type (n = 33) and extrasynaptic δ-subunit-containing GABAAR knockout mice (n = 9) during bilateral microperfusion of the thalamus with etomidate and/or other pharmacologic agents that influence GABAAR or T-type Ca channel activity.

RESULTS: Microperfusion of etomidate into the thalamus elicited an increase in α-β frequency electrocortical activity that occurred only during non-rapid-eye-movement (REM) sleep (11.0 ± 11.8% and 16.0 ± 14.2% greater 8 to 12- and 12 to 30-Hz power, respectively; mean ± SD; both P < 0.031) and was not affected by blockade of thalamic T-type Ca channels. Etomidate at the thalamus also increased spindle-like oscillations during non-REM sleep (4.5 ± 2.4 spindle per minute with etomidate vs. 3.2 ± 1.7 at baseline; P = 0.002). These effects of etomidate were fully recapitulated by enhanced thalamic extrasynaptic GABAAR-mediated spillover inhibition.

CONCLUSIONS: These findings identify how a prototypic GABAAR-targeting general anesthetic agent can elicit the characteristic brain wave pattern associated with anesthetic hypnosis when acting at the thalamus by promoting spillover inhibition and the necessity of a preexisting non-REM mode of activity in the thalamus to generate this effect.