title: Nicotinic enhancement of the noradrenergic inhibition of sleep-promoting neurons in the ventrolateral preoptic area.
abstract: According to multiple lines of evidence, neurons in the ventrolateral preoptic area (VLPO) that contain GABA promote sleep by inhibiting neurons of the arousal systems. Reciprocally, transmitters used by these systems, including acetylcholine (ACh) and noradrenaline (NA), exert an inhibitory action on the VLPO neurons. Because nicotine, an agonist of ACh, acts as a potent stimulant, we queried whether it might participate in the cholinergic inhibition of these sleep-promoting cells. Indeed, we found that ACh inhibits the VLPO neurons through a nicotinic, as well as a muscarinic, action. As evident in the presence of atropine, the non-muscarinic component was mimicked by epibatidine, a nonselective nicotinic ACh receptor (nAChR) agonist and was blocked by dihydro-beta-erythroidine, a nonselective nAChR antagonist. It was not, however, blocked by methyllycaconitine, a selective antagonist of the alpha7 subtype, indicating that the action was mediated by non-alpha7 nAChRs. The nicotinic inhibition was attributed to a presynaptic facilitation of NA release because it persisted in the presence of tetrodotoxin and was blocked by yohimbine and RS 79948, which are both selective antagonists of alpha2 adrenergic receptors. Sleep-promoting VLPO neurons are thus dually inhibited by ACh through a muscarinic postsynaptic action and a nicotinic presynaptic action on noradrenergic terminals. Such dual complementary actions allow ACh and nicotine to enhance wakefulness by inhibiting sleep-promoting systems while facilitating other wake-promoting systems.
authors.affiliation: Département de Physiologie, Centre Médical Universitaire, 1211 Geneva 4, Switzerland.
authors.forename: Benoît
authors.initials: B
authors.lastname: Saint-Mleux
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Eggermann
authors.forename: Arnaud
authors.initials: A
authors.lastname: Bisetti
authors.forename: Laurence
authors.initials: L
authors.lastname: Bayer
authors.forename: Danièle
authors.initials: D
authors.lastname: Machard
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Jones
authors.forename: Michel
authors.initials: M
authors.lastname: Mühlethaler
authors.forename: Mauro
authors.initials: M
authors.lastname: Serafin
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D004357:Drug Synergism; D004553:Electric Conductivity; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009433:Neural Inhibition; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000378:metabolism; D011301:Preoptic Area / Q000033:anatomy & histology / Q000166:cytology / Q000502:physiology*; D017729:Presynaptic Terminals / Q000378:metabolism; D051381:Rats; D011976:Receptors, Muscarinic / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism; D012890:Sleep / Q000502:physiology
chemical_list: D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D018722:Nicotinic Agonists; D015221:Potassium Channels; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; D000109:Acetylcholine; D009638:Norepinephrine