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Cited by 123Nicotinic Acetylcholine Receptors StudySmoking Behavior and CessationNeurotransmitter Receptor Influence on Behavior

Nicotine consumption is regulated by a human polymorphism in dopamine neurons

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Morel, C, Fattore, L, Pons, S, Hay, Y A, Marti, F, Lambolez, B, De Biasi, M, Lathrop, M +3 more·2014·Molecular Psychiatry
DOI 10.1038/mp.2013.158PMC PMC8596967
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Abstract

Smoking is the most important preventable cause of morbidity and mortality worldwide. Recent genome-wide association studies highlighted a human haplotype on chromosome 15 underlying the risk for tobacco dependence and lung cancer. Several polymorphisms in the CHRNA3-CHRNA5-CHRNB4 cluster coding for the nicotinic acetylcholine receptor (nAChR) α3, α5 and β4 subunits were implicated. In mouse models, we define a key role in the control of sensitivity to nicotine for the α5 subunit in dopaminergic (DAergic) neurons of the ventral tegmental area (VTA). We first investigated the reinforcing effects of nicotine in drug-naive α5(-/-) mice using an acute intravenous nicotine self-administration task and ex vivo and in vivo electrophysiological recordings of nicotine-elicited DA cell activation. We designed lentiviral re-expression vectors to achieve targeted re-expression of wild-type or mutant α5 in the VTA, in general, or in DA neurons exclusively. Our results establish a crucial role for α5*-nAChRs in DAergic neurons. These receptors are key regulators that determine the minimum nicotine dose necessary for DA cell activation and thus nicotine reinforcement. Finally, we demonstrate that a single-nucleotide polymorphism, the non-synonymous α5 variant rs16969968, frequent in many human populations, exhibits a partial loss of function of the protein in vivo. This leads to increased nicotine consumption in the self-administration paradigm. We thus define a critical link between a human predisposition marker, its expression in DA neurons and nicotine intake.

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  • The impact of the mutation defining the risk allele has been validated repeatedly in vitro and in animal models.

    “The impact of the mutation that defines the risk allele has been validated repeatedly in vitro and in animal models (Kuryatov et al. 2011; Morel et al. 2014).”

    From Nicotine Withdrawal (2015) · cites this paper as Morel et al. 2014

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Authors
Morel, C., Fattore, L., Pons, S., Hay, Y. A., Marti, F., Lambolez, B., De Biasi, M., Lathrop, M., Fratta, W., Maskos, U., & Faure, P.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • National Research Council (IT)
  • Fondation Jean Dausset-CEPH (FR)
  • University of Cagliari (IT)
Corresponding author
Maskos, U
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2013-12-03
Volume
19
Issue
8
Pages
930-936
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/mp.2013.158
PMC
PMC8596967
OpenAlex
W2010762896
Cited by
123
References
8
Citations by year
2026: 1 · 2025: 10 · 2024: 8 · 2023: 5 · 2022: 8 · 2021: 6 · 2020: 8 · 2019: 11 · 2018: 17 · 2017: 11 · 2016: 13 · 2015: 17 · 2014: 8
FWCI
5.68
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • HAL (submittedVersion)
  • UNICA IRIS Institutional Research Information System (University of Cagliari) (submittedVersion)
Funders
  • National Institute on Drug Abuse (R21DA029157, DA029157)
  • National Cancer Institute (U19CA148127)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
  • Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
nicotine self-administration, nicotinic acetylcholine receptors, CHRNA5, dopaminergic neurons, ventral tegmental area, nicotine reinforcement, rs16969968, single nucleotide polymorphisms, loss-of-function mutations, tobacco dependence, nicotine sensitivity
MeSH terms
Action Potentials, Animals, Male, Nicotine, Receptors, Nicotinic, Reinforcement, Psychology, Self Administration, Ventral Tegmental Area, Mice, Knockout, Polymorphism, Single Nucleotide, Mice, Dopaminergic Neurons

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