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Nat Neurosci. 2017 May;20(5):708-716. doi: 10.1038/nn.4540. Epub 2017 Apr 3.

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

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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.
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Autism Speaks, Boston, Massachusetts, USA.


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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