title: Modulation of vigilance in the primary hypersomnias by endogenous enhancement of GABAA receptors.
abstract: The biology underlying excessive daytime sleepiness (hypersomnolence) is incompletely understood. After excluding known causes of sleepiness in 32 hypersomnolent patients, we showed that, in the presence of 10 μM γ-aminobutyric acid (GABA), cerebrospinal fluid (CSF) from these subjects stimulated GABA(A) receptor function in vitro by 84.0 ± 40.7% (SD) relative to the 35.8 ± 7.5% (SD) stimulation obtained with CSF from control subjects (Student's t test, t = 6.47, P < 0.0001); CSF alone had no effect on GABA(A) signaling. The bioactive CSF component had a mass of 500 to 3000 daltons and was neutralized by trypsin. Enhancement was greater for α2 subunit- versus α1 subunit-containing GABA(A) receptors and negligible for α4 subunit-containing ones. CSF samples from hypersomnolent patients also modestly enhanced benzodiazepine (BZD)-insensitive GABA(A) receptors and did not competitively displace BZDs from human brain tissue. Flumazenil--a drug that is generally believed to antagonize the sedative-hypnotic actions of BZDs only at the classical BZD-binding domain in GABA(A) receptors and to lack intrinsic activity--nevertheless reversed enhancement of GABA(A) signaling by hypersomnolent CSF in vitro. Furthermore, flumazenil normalized vigilance in seven hypersomnolent patients. We conclude that a naturally occurring substance in CSF augments inhibitory GABA signaling, thus revealing a new pathophysiology associated with excessive daytime sleepiness.
authors.affiliation: Department of Neurology, Program in Sleep, Emory University School of Medicine, Atlanta, GA 30322, USA. drye@emory.edu
authors.forename: David B
authors.initials: DB
authors.lastname: Rye
authors.forename: Donald L
authors.initials: DL
authors.lastname: Bliwise
authors.forename: Kathy
authors.initials: K
authors.lastname: Parker
authors.forename: Lynn Marie
authors.initials: LM
authors.lastname: Trotti
authors.forename: Prabhjyot
authors.initials: P
authors.lastname: Saini
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Fairley
authors.forename: Amanda
authors.initials: A
authors.lastname: Freeman
authors.forename: Paul S
authors.initials: PS
authors.lastname: Garcia
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owens
authors.forename: James C
authors.initials: JC
authors.lastname: Ritchie
authors.forename: Andrew
authors.initials: A
authors.lastname: Jenkins
mesh_terms: D000328:Adult; D001143:Arousal / Q000187:drug effects; D001519:Behavior / Q000187:drug effects; D018118:Chloride Channels / Q000378:metabolism; D006970:Disorders of Excessive Somnolence / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000453:epidemiology / Q000503:physiopathology*; D005260:Female; D005442:Flumazenil / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D011963:Receptors, GABA-A / Q000378:metabolism*; D015203:Reproducibility of Results
chemical_list: D018118:Chloride Channels; D011963:Receptors, GABA-A; D005442:Flumazenil