title: GLP-1 acts on habenular avoidance circuits to control nicotine intake.
abstract: Tobacco smokers titrate their nicotine intake to avoid its noxious effects, sensitivity to which may influence vulnerability to tobacco dependence, yet mechanisms of nicotine avoidance are poorly understood. Here we show that nicotine activates glucagon-like peptide-1 (GLP-1) neurons in the nucleus tractus solitarius (NTS). The antidiabetic drugs sitagliptin and exenatide, which inhibit GLP-1 breakdown and stimulate GLP-1 receptors, respectively, decreased nicotine intake in mice. Chemogenetic activation of GLP-1 neurons in NTS similarly decreased nicotine intake. Conversely, Glp1r knockout mice consumed greater quantities of nicotine than wild-type mice. Using optogenetic stimulation, we show that GLP-1 excites medial habenular (MHb) projections to the interpeduncular nucleus (IPN). Activation of GLP-1 receptors in the MHb-IPN circuit abolished nicotine reward and decreased nicotine intake, whereas their knockdown or pharmacological blockade increased intake. GLP-1 neurons may therefore serve as 'satiety sensors' for nicotine that stimulate habenular systems to promote nicotine avoidance before its aversive effects are encountered.
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute Jupiter, Florida, USA.|The Kellogg School of Science and Technology, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Luis M
authors.initials: LM
authors.lastname: Tuesta
authors.affiliation: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Zuxin
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Duncan
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute Jupiter, Florida, USA.
authors.forename: Christie D
authors.initials: CD
authors.lastname: Fowler
authors.affiliation: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Masago
authors.initials: M
authors.lastname: Ishikawa
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute Jupiter, Florida, USA.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Lee
authors.affiliation: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Xin-An
authors.initials: XA
authors.lastname: Liu
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute Jupiter, Florida, USA.
authors.forename: Qun
authors.initials: Q
authors.lastname: Lu
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute Jupiter, Florida, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Cameron
authors.affiliation: Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Hayes
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute Jupiter, Florida, USA.
authors.forename: Theodore M
authors.initials: TM
authors.lastname: Kamenecka
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute Jupiter, Florida, USA.|Autism Speaks, Boston, Massachusetts, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Pletcher
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute Jupiter, Florida, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kenny
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000502:physiology*; D000077270:Exenatide; D005260:Female; D055785:Gene Knockdown Techniques; D052216:Glucagon-Like Peptide 1 / Q000502:physiology*; D000067757:Glucagon-Like Peptide-1 Receptor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D019262:Habenula / Q000502:physiology*; D066268:Interpeduncular Nucleus / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009434:Neural Pathways / Q000502:physiology; D009538:Nicotine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D012201:Reward; D012653:Self Stimulation; D000068900:Sitagliptin Phosphate / Q000494:pharmacology; D017552:Solitary Nucleus / Q000502:physiology; D014688:Venoms / Q000494:pharmacology; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D014688:Venoms; D009538:Nicotine; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D000068900:Sitagliptin Phosphate; D000097789:Glucagon-Like Peptide-1 Receptor Agonists