title: Enhanced tonic inhibition influences the hypnotic and amnestic actions of the intravenous anesthetics etomidate and propofol.
abstract: Intravenous anesthetics exert a component of their actions via potentiating inhibitory neurotransmission mediated by γ-aminobutyric type-A receptors (GABAARs). Phasic and tonic inhibition is mediated by distinct populations of GABAARs, with the majority of phasic inhibition by subtypes composed of α1-3βγ2 subunits, whereas tonic inhibition is dependent on subtypes assembled from α4-6βδ subunits. To explore the contribution that these distinct forms of inhibition play in mediating intravenous anesthesia, we have used mice in which tyrosine residues 365/7 within the γ2 subunit are mutated to phenyalanines (Y365/7F). Here we demonstrate that this mutation leads to increased accumulation of the α4 subunit containing GABAARs in the thalamus and dentate gyrus of female Y365/7F but not male Y365/7F mice. Y365/7F mice exhibited a gender-specific enhancement of tonic inhibition in the dentate gyrus that was more sensitive to modulation by the anesthetic etomidate, together with a deficit in long-term potentiation. Consistent with this, female Y365/7F, but not male Y365/7F, mice exhibited a dramatic increase in the duration of etomidate- and propofol-mediated hypnosis. Moreover, the amnestic actions of etomidate were selectively potentiated in female Y365/7F mice. Collectively, these observations suggest that potentiation of tonic inhibition mediated by α4 subunit containing GABAARs contributes to the hypnotic and amnestic actions of the intravenous anesthetics, etomidate and propofol.
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
authors.forename: Karla
authors.initials: K
authors.lastname: Kretschmannova
authors.forename: Rochelle M
authors.initials: RM
authors.lastname: Hines
authors.forename: Raquel
authors.initials: R
authors.lastname: Revilla-Sanchez
authors.forename: Miho
authors.initials: M
authors.lastname: Terunuma
authors.forename: Verena
authors.initials: V
authors.lastname: Tretter
authors.forename: Rachel
authors.initials: R
authors.lastname: Jurd
authors.forename: Max B
authors.initials: MB
authors.lastname: Kelz
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Moss
authors.forename: Paul A
authors.initials: PA
authors.lastname: Davies
mesh_terms: D000647:Amnesia / Q000139:chemically induced* / Q000503:physiopathology; D018686:Anesthetics, Intravenous / Q000008:administration & dosage; D000818:Animals; D005045:Etomidate / Q000008:administration & dosage*; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006993:Hypnotics and Sedatives / Q000008:administration & dosage*; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology; D009924:Organ Culture Techniques; D015742:Propofol / Q000008:administration & dosage*; D011897:Random Allocation
chemical_list: D018686:Anesthetics, Intravenous; D006993:Hypnotics and Sedatives; D015742:Propofol; D005045:Etomidate