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

Nature Neuroscience volume 20, pages 708716 (2017) | Download Citation

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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.

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Change history

  • 10 April 2017

    In the version of this article initially published online, the original source of the Glp1r knockout mice, D.J. Drucker (Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto), was not acknowledged. The error has been corrected in the print, PDF and HTML versions of this article.

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Acknowledgements

We thank D.J. Drucker (Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto) for providing the Glp1r knockout mice. This work was supported by the US National Institutes of Health (DA032225 to L.M.T., DK096139 to M.R.H., DA020686 to P.J.K.).

Author information

Author notes

    • Luis M Tuesta
    •  & Paul J Kenny

    Present addresses: Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA (L.M.T.) and Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA (P.J.K.).

Affiliations

  1. Department of Molecular Therapeutics, The Scripps Research Institute Jupiter, Florida, USA.

    • Luis M Tuesta
    • , Christie D Fowler
    • , Brian R Lee
    • , Qun Lu
    • , Michael Cameron
    • , Theodore M Kamenecka
    • , Matthew Pletcher
    •  & Paul J Kenny
  2. The Kellogg School of Science and Technology, The Scripps Research Institute, Jupiter, Florida, USA.

    • Luis M Tuesta
  3. Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Zuxin Chen
    • , Alexander Duncan
    • , Masago Ishikawa
    •  & Xin-An Liu
  4. Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Matthew R Hayes
  5. Autism Speaks, Boston, Massachusetts, USA.

    • Matthew Pletcher

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Contributions

L.M.T., A.D., Z.C., C.D.F., B.R.L., X.-A.L., Q.L. and M.I. conducted all experiments. T.M.K., M.C., M.P. and M.R.H. provided essential reagents. L.M.T. and P.J.K. designed the experiments, analyzed the data and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Paul J Kenny.

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DOI

https://doi.org/10.1038/nn.4540

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