title: α2-Adrenergic stimulation of the ventrolateral preoptic nucleus destabilizes the anesthetic state.
abstract: The sleep-promoting ventrolateral preoptic nucleus (VLPO) shares reciprocal inhibitory inputs with wake-active neuronal nuclei, including the locus ceruleus. Electrophysiologically, sleep-promoting neurons in the VLPO are directly depolarized by the general anesthetic isoflurane and hyperpolarized by norepinephrine, a wake-promoting neurotransmitter. However, the integration of these competing influences on the VLPO, a sleep- and anesthetic-active structure, has yet to be evaluated in either brain slices in vitro or the intact organism. Single-cell multiplex RT-PCR conducted on both isoflurane-activated, putative sleep-promoting VLPO neurons and neighboring, state-indifferent VLPO neurons in mouse brain slices revealed widespread expression of α2A-, α2B- and α2C-adrenergic receptors in both populations. Indeed, both norepinephrine and the highly selective α2 agonist dexmedetomidine each reversed the VLPO depolarization induced by isoflurane in slices in vitro. When microinjected directly into the VLPO of a mouse lightly anesthetized with isoflurane, dexmedetomidine increased behavioral arousal and reduced the depressant effects of isoflurane on barrel cortex somatosensory-evoked potentials but failed to elicit spectral changes in spontaneous EEG. Based on these observations, we conclude that local modulation of α-adrenergic activity in the VLPO destabilizes, but does not fully antagonize, the anesthetic state, thus priming the brain for anesthetic emergence.
authors.affiliation: Departments of Anesthesiology and Critical Care, Pharmacology, and Center for Sleep and Circadian Neurobiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, and.
authors.forename: Hilary S
authors.initials: HS
authors.lastname: McCarren
authors.affiliation: Departments of Anesthesiology and Critical Care.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Chalifoux
authors.affiliation: Departments of Anesthesiology and Critical Care.
authors.forename: Bo
authors.initials: B
authors.lastname: Han
authors.affiliation: Departments of Anesthesiology and Critical Care.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Moore
authors.affiliation: Departments of Anesthesiology and Critical Care.
authors.forename: Qing Cheng
authors.initials: QC
authors.lastname: Meng
authors.affiliation: Neuroscience and.
authors.forename: Nina
authors.initials: N
authors.lastname: Baron-Hionis
authors.affiliation: Neuroscience and.
authors.forename: Madineh
authors.initials: M
authors.lastname: Sedigh-Sarvestani
authors.affiliation: Neuroscience and.
authors.forename: Diego
authors.initials: D
authors.lastname: Contreras
authors.affiliation: Departments of Anesthesiology and Critical Care, Pharmacology, and Institute for Translational Medicine and Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, Department of Anesthesiology and Critical Care, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.
authors.forename: Sheryl G
authors.initials: SG
authors.lastname: Beck
authors.affiliation: Departments of Anesthesiology and Critical Care, Pharmacology, and Institute for Translational Medicine and Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, Department of Anesthesiology and Critical Care, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104 kelzma@uphs.upenn.edu.
authors.forename: Max B
authors.identifier: http://orcid.org/0000-0002-2803-6078
authors.initials: MB
authors.lastname: Kelz
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology; D000777:Anesthetics / Q000494:pharmacology; D000818:Animals; D001143:Arousal / Q000187:drug effects*; D058256:Brain Waves / Q000187:drug effects; D020927:Dexmedetomidine / Q000008:administration & dosage / Q000494:pharmacology; D004569:Electroencephalography; D005073:Evoked Potentials, Somatosensory / Q000187:drug effects / Q000502:physiology; D007530:Isoflurane / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008845:Microinjections; D009638:Norepinephrine / Q000494:pharmacology; D011301:Preoptic Area / Q000187:drug effects / Q000502:physiology*; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism / Q000502:physiology*
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D000777:Anesthetics; D018341:Receptors, Adrenergic, alpha-2; D020927:Dexmedetomidine; D007530:Isoflurane; D009638:Norepinephrine
keywords: VLPO; adrenergic; anesthesia; dexmedetomidine; emergence; sleep