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	Luis M Tuesta, Zuxin Chen, Alexander Duncan, Christie D Fowler, Masago Ishikawa, Brian R Lee, Xin-An Liu, Qun Lu, Michael Cameron, Matthew R Hayes, Theodore M Kamenecka, Matthew Pletcher, Paul J Kenny
Journal	Nature neuroscience (Nat Neurosci) Vol. 20 Issue 5 Pg. 708-716 (May 2017) ISSN: 1546-1726 [Electronic] United States
PMID	28368384 (Publication Type: Journal Article)
Chemical References	Glucagon-Like Peptide-1 Receptor Peptides Venoms Nicotine Glucagon-Like Peptide 1 Exenatide Sitagliptin Phosphate
Topics	Animals Avoidance Learning (physiology) Exenatide Female Gene Knockdown Techniques Glucagon-Like Peptide 1 (physiology) Glucagon-Like Peptide-1 Receptor (agonists, antagonists & inhibitors, genetics, physiology) Habenula (physiology) Interpeduncular Nucleus (physiology) Male Mice Mice, Knockout Neural Pathways (physiology) Nicotine (antagonists & inhibitors, pharmacology) Peptides (pharmacology) Rats Reward Self Stimulation Sitagliptin Phosphate (pharmacology) Solitary Nucleus (physiology) Venoms (pharmacology)

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