GLP-1 acts on habenular avoidance circuits to control nicotine intake

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

doi:10.1038/nn.4540

GLP-1 acts on habenular avoidance circuits to control nicotine intake

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

Research output: Contribution to journal › Article › peer-review

127 Scopus citations

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.

Original language	English
Pages (from-to)	708-716
Number of pages	9
Journal	Nature Neuroscience
Volume	20
Issue number	5
DOIs	https://doi.org/10.1038/nn.4540
State	Published - 1 May 2017

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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.",

author = "Tuesta, {Luis M.} and Zuxin Chen and Alexander Duncan and Fowler, {Christie D.} and Masago Ishikawa and Lee, {Brian R.} and Liu, {Xin An} and Qun Lu and Michael Cameron and Hayes, {Matthew R.} and Kamenecka, {Theodore M.} and Matthew Pletcher and Kenny, {Paul J.}",

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AU - Tuesta, Luis M.

AU - Chen, Zuxin

AU - Duncan, Alexander

AU - Fowler, Christie D.

AU - Ishikawa, Masago

AU - Lee, Brian R.

AU - Liu, Xin An

AU - Lu, Qun

AU - Cameron, Michael

AU - Hayes, Matthew R.

AU - Kamenecka, Theodore M.

AU - Pletcher, Matthew

AU - Kenny, Paul J.

PY - 2017/5/1

Y1 - 2017/5/1

N2 - 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.

AB - 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.

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GLP-1 acts on habenular avoidance circuits to control nicotine intake

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