The sedative component of anesthesia is mediated by GABAA receptors in an endogenous sleep pathway

Abstract

We investigated the role of regionally discrete GABA (gamma-aminobutyric acid) receptors in the sedative response to pharmacological agents that act on GABA(A) receptors (muscimol, propofol and pentobarbital; 'GABAergic agents') and to ketamine, a general anesthetic that does not affect GABA(A) receptors. Behavioral studies in rats showed that the sedative response to centrally administered GABAergic agents was attenuated by the GABA(A) receptor antagonist gabazine (systemically administered). The sedative response to ketamine, by contrast, was unaffected by gabazine. Using c-Fos as a marker of neuronal activation, we identified a possible role for the tuberomammillary nucleus (TMN): when gabazine was microinjected directly into the TMN, it attenuated the sedative response to GABAergic agents. Furthermore, the GABA(A) receptor agonist muscimol produced a dose-dependent sedation when it was administered into the TMN. We conclude that the TMN is a discrete neural locus that has a key role in the sedative response to GABAergic anesthetics.

Posterior cingulate, precuneal and retrosplenial cortices: cytology and components of the neural network correlates of consciousness

“…In the rat, the tuberomamillary nucleus is particularly sensitive to anesthetics that act at GABA A receptors including propofol (Nelson et al, 2002). Although the rat has a well differentiated RSC, it does not have areas 23, 31, or 7m (Vogt et al, 2004) and the tuberomamillary nucleus does not project to RSC in rat or monkey brain.…”

Lesion of cholinergic neurons in nucleus basalis enhances response to general anesthetics

“…Inactivation of the medial septum, hippocampus, nucleus accumbens, ventral pallidum, ventral tegmental area and supramammillary area prolonged the LORR induced by both pentobarbital and halothane (Ma et al, 2002;Ma and Leung, 2006), while inactivation of the entorhinal cortex and piriform cortex mainly prolonged the LORR induced by pentobarbital but not halothane (Long et al, 2009). Infusion of muscimol into the mesopontine tegmentum (Devor and Zalkind, 2001) or tuberomammillary nucleus (Nelson et al, 2002) may induce LORR. Like the NBM, inactivation of a brain structure may enhance general anesthetic responses by influencing sleep-wake circuits.…”

“…Despite advances made on the molecular action of various general anesthetics, such as their action on K + channels, GABA A , nicotinic and glutamate receptors (Franks, 2008), brain structures underlying general anesthesia remain unclear. Anesthetic-induced loss of consciousness was enhanced if arousal related brain structures were ablated or inactivated (Devor and Zalkind, 2001;Nelson et al, 2002;Flint et al, 2010;Franks, 2008;Kelz et al, 2008;Lu et al, 2008;Luo and Leung, 2009), and sleep deprivation increased the potency of propofol and isoflurane (Tung et al, 2002).…”

Nitrous oxide (N 2 O) requires the N -methyl- d -aspartate receptor for its action in Caenorhabditis elegans

“…Pharmacological and genetic methods are the means by which this question of relevancy can be answered. GABA A and glycine receptor antagonists produce a rightward shift in the doseresponse curves for VAs (14,15); however, substantial effects of clinical concentrations of VAs are still produced. Importantly, these results support the hypothesis that potentiation of these receptors is part of the mechanism of anesthesia for VAs, but they also demonstrate that the receptors are not the only targets.…”