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Habenular α5 nicotinic receptor subunit signalling controls nicotine intake

Author

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  • Christie D. Fowler

    (Laboratory for Behavioral and Molecular Neuroscience, The Scripps Research Institute—Scripps Florida)

  • Qun Lu

    (Laboratory for Behavioral and Molecular Neuroscience, The Scripps Research Institute—Scripps Florida)

  • Paul M. Johnson

    (Laboratory for Behavioral and Molecular Neuroscience, The Scripps Research Institute—Scripps Florida)

  • Michael J. Marks

    (Institute of Behavioral Genetics, University of Colorado)

  • Paul J. Kenny

    (Laboratory for Behavioral and Molecular Neuroscience, The Scripps Research Institute—Scripps Florida)

Abstract

Genetic variation in CHRNA5, the gene encoding the α5 nicotinic acetylcholine receptor subunit, increases vulnerability to tobacco addiction and lung cancer, but the underlying mechanisms are unknown. Here we report markedly increased nicotine intake in mice with a null mutation in Chrna5. This effect was ‘rescued’ in knockout mice by re-expressing α5 subunits in the medial habenula (MHb), and recapitulated in rats through α5 subunit knockdown in MHb. Remarkably, α5 subunit knockdown in MHb did not alter the rewarding effects of nicotine but abolished the inhibitory effects of higher nicotine doses on brain reward systems. The MHb extends projections almost exclusively to the interpeduncular nucleus (IPN). We found diminished IPN activation in response to nicotine in α5 knockout mice. Further, disruption of IPN signalling increased nicotine intake in rats. Our findings indicate that nicotine activates the habenulo-interpeduncular pathway through α5-containing nAChRs, triggering an inhibitory motivational signal that acts to limit nicotine intake.

Suggested Citation

  • Christie D. Fowler & Qun Lu & Paul M. Johnson & Michael J. Marks & Paul J. Kenny, 2011. "Habenular α5 nicotinic receptor subunit signalling controls nicotine intake," Nature, Nature, vol. 471(7340), pages 597-601, March.
    • Handle: RePEc:nat:nature:v:471:y:2011:i:7340:d:10.1038_nature09797
    DOI: 10.1038/nature09797
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    Cited by:

    1. Hiroyuki Kawai & Youcef Bouchekioua & Naoya Nishitani & Kazuhei Niitani & Shoma Izumi & Hinako Morishita & Chihiro Andoh & Yuma Nagai & Masashi Koda & Masako Hagiwara & Koji Toda & Hisashi Shirakawa &, 2022. "Median raphe serotonergic neurons projecting to the interpeduncular nucleus control preference and aversion," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    2. Susanna Molas & Timothy G. Freels & Rubing Zhao-Shea & Timothy Lee & Pablo Gimenez-Gomez & Melanie Barbini & Gilles E. Martin & Andrew R. Tapper, 2024. "Dopamine control of social novelty preference is constrained by an interpeduncular-tegmentum circuit," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Andrew C. Harris & John R. Smethells & Mary Palumbo & Maciej Goniewicz & Mark G. LeSage, 2020. "Comparison of the Relative Abuse Liability of Electronic Cigarette Aerosol Extracts and Nicotine Alone in Adolescent Rats: A Behavioral Economic Analysis," IJERPH, MDPI, vol. 17(3), pages 1-12, January.

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