title: Brainstem node for loss of consciousness due to GABA(A) receptor-active anesthetics.
abstract: The molecular agents that induce loss of consciousness during anesthesia are classically believed to act by binding to cognate transmembrane receptors widely distributed in the CNS and critically suppressing local processing and network connectivity. However, previous work has shown that microinjection of anesthetics into a localized region of the brainstem mesopontine tegmentum (MPTA) rapidly and reversibly induces anesthesia in the absence of global spread. This implies that functional extinction is determined by neural pathways rather than vascular distribution of the anesthetic agent. But does clinical (systemic-induced) anesthesia employ MPTA-linked circuitry? Here we show that cell-selective lesioning of the MPTA in rats does not, in itself, induce anesthesia or coma. However, it increases the systemic dose of pentobarbital required to induce anesthesia, in a manner proportional to the extent of the lesion. Such lesions also affect emergence, extending the duration of anesthesia. Off-target and sham lesions were ineffective. Combined with the prior microinjection data, we conclude that drug delivery to the MPTA is sufficient to induce loss-of-consciousness and that neurons in this locus are necessary for anesthetic induction at clinically relevant doses. Together, the results support an architecture for anesthesia with the MPTA serving as a key node in an endogenous network of dedicated pathways that switch between wake and unconsciousness. As such, the MPTA might also play a role in syncope, concussion and sleep.
authors.affiliation: Department of Cell and Developmental Biology, Institute of Life Sciences and the Center for Research on Pain, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
authors.forename: Anne
authors.initials: A
authors.lastname: Minert
authors.affiliation: Department of Cell and Developmental Biology, Institute of Life Sciences and the Center for Research on Pain, The Hebrew University of Jerusalem, Jerusalem 91904, Israel. Electronic address: marshlu@mail.huji.ac.il.
authors.forename: Marshall
authors.initials: M
authors.lastname: Devor
mesh_terms: D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D001933:Brain Stem / Q000187:drug effects* / Q000502:physiology; D018757:GABA Modulators / Q000494:pharmacology*; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D008297:Male; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology; D010424:Pentobarbital / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000502:physiology*; D014474:Unconsciousness / Q000503:physiopathology
chemical_list: D000777:Anesthetics; D018757:GABA Modulators; D006993:Hypnotics and Sedatives; D011963:Receptors, GABA-A; D010424:Pentobarbital
keywords: Brainstem; Coma; Concussion; General anesthesia; Loss-of-consciousness; MPTA