title: Disinhibition of perifornical hypothalamic neurones activates noradrenergic neurones and blocks pontine carbachol-induced REM sleep-like episodes in rats.
abstract: Studies in behaving animals suggest that neurones located in the perifornical (PF) region of the posterior hypothalamus promote wakefulness and suppress sleep. Among such cells are those that synthesize the excitatory peptides, orexins (ORX). Lack of ORX, or their receptors, is associated with narcolepsy/cataplexy, a disorder characterized by an increased pressure for rapid eye movement (REM) sleep. We used anaesthetized rats in which pontine microinjections of a cholinergic agonist, carbachol, can repeatedly elicit REM sleep-like episodes to test whether activation of PF cells induced by antagonism of endogenous, GABA(A) receptor-mediated, inhibition suppresses the ability of the brainstem to generate REM sleep-like state. Microinjections of the GABA(A) receptor antagonist, bicuculline (20 nl, 1 mm), into the PF region elicited cortical and hippocampal activation, increased the respiratory rate and hypoglossal nerve activity, induced c-fos expression in ORX and other PF neurones, and increased c-fos expression in pontine A7 and other noradrenergic neurones. The ability of pontine carbachol to elicit any cortical, hippocampal or brainstem component of the REM sleep-like response was abolished during the period of bicuculline-induced activation. The activating and REM sleep-suppressing effect of PF bicuculline was not attenuated by systemic administration of the ORX type 1 receptor antagonist, SB334867. Thus, activation of PF neurones that are endogenously inhibited by GABA(A) receptors is sufficient to turn off the brainstem REM sleep-generating network; the effect is, at least in part, due to activation of pontine noradrenergic neurones, but is not mediated by ORX type 1 receptors. A malfunction of the pathway that originates in GABA(A) receptor-expressing PF neurones may cause narcolepsy/cataplexy.
authors.affiliation: Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA 19104-6046, USA.
authors.forename: Jackie W
authors.initials: JW
authors.lastname: Lu
authors.forename: Victor B
authors.initials: VB
authors.lastname: Fenik
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Branconi
authors.forename: Graziella L
authors.initials: GL
authors.lastname: Mann
authors.forename: Irma
authors.initials: I
authors.lastname: Rukhadze
authors.forename: Leszek
authors.initials: L
authors.lastname: Kubin
mesh_terms: D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology; D001640:Bicuculline / Q000008:administration & dosage / Q000494:pharmacology; D002217:Carbachol / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D020712:Fornix, Brain; D018756:GABA Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D007031:Hypothalamus / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D007267:Injections; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D008297:Male; D009287:Naphthyridines; D009433:Neural Inhibition / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D009479:Neuropeptides / Q000502:physiology; D009638:Norepinephrine / Q000378:metabolism*; D064446:Orexin Receptors; D000068797:Orexins; D011149:Pons / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors; D012895:Sleep, REM / Q000187:drug effects / Q000502:physiology*; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D001583:Benzoxazoles; D018756:GABA Antagonists; D047908:Intracellular Signaling Peptides and Proteins; D009287:Naphthyridines; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D014508:Urea; D002217:Carbachol; D009638:Norepinephrine; D001640:Bicuculline