Neurosteroids foster sedation by engaging tonic GABAA-Rs within the mesopontine tegmental anesthesia area (MPTA)

Abstract

Neurosteroids are endogenous molecules with anxiolytic, anticonvulsant, sleep-promoting and sedative effects. They are biosynthesized de novo within the brain, among other tissues, and are thought to act primarily as positive allosteric modulators of high-affinity extrasynaptic GABA_Aδ-receptors. The location of action of neurosteroids in the brain, however, remains unknown. We have demonstrated that GABAergic anesthetics act within the brainstem mesopontine tegmental anesthesia area (MPTA) to induce and maintain anesthetic loss-of-consciousness. Here we asked whether endogenous and synthetic neurosteroids might also act in the MPTA to induce their suppressive effects. Direct exposure of the MPTA to the endogenous neurosteroids pregnenolone and progesterone, their metabolites testosterone, allopregnanolone and 3α5α-THDOC, and the synthetic neurosteroids ganaxolone and alphaxalone, was found to be pro-anesthetic. Although we cannot rule out additional sites of action, results of this study suggest that the suppressive effects of neurosteroids are due, at least in part, to actions within the MPTA, presumably by recruitment of dedicated neuronal circuitry. This undermines the usual presumption that neurosteroids, like other sedatives, endogenous somnogens and anesthetics, act by nonspecific global distribution.