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Distinct contributions of nicotinic acetylcholine receptor subunit α4 and subunit α6 to the reinforcing effects of nicotine
Open accessAbstract
Nicotine is the primary psychoactive component of tobacco. Its reinforcing and addictive properties depend on nicotinic acetylcholine receptors (nAChRs) located within the mesolimbic axis originating in the ventral tegmental area (VTA). The roles and oligomeric assembly of subunit α4- and subunit α6-containing nAChRs in dopaminergic (DAergic) neurons are much debated. Using subunit-specific knockout mice and targeted lentiviral re-expression, we have determined the subunit dependence of intracranial nicotine self-administration (ICSA) into the VTA and the effects of nicotine on dopamine (DA) neuron excitability in the VTA and on DA transmission in the nucleus accumbens (NAc). We show that the α4 subunit, but not the α6 subunit, is necessary for ICSA and nicotine-induced bursting of VTA DAergic neurons, whereas subunits α4 and α6 together regulate the activity dependence of DA transmission in the NAc. These data suggest that α4-dominated enhancement of burst firing in DA neurons, relayed by DA transmission in NAc that is gated by nAChRs containing α4 and α6 subunits, underlies nicotine self-administration and its long-term maintenance.
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“Similarly, knockout of the α4 subunit abolishes intracerebroventricular (i.c.v.) selfadministration of nicotine, consistent with evidence that α4/β2 Ã nAChRs are required for depolarization of DA neurons in the VTA (Exley et al. 2011;McGranahan et al. 2011).”
From Mechanisms of Nicotine Addiction (2021) · cites this paper as Exley et al. 2011
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“In contrast, in mice with constitutive knockout of the α6 subunit, intra-VTA selfadministration of nicotine is not disrupted, whereas α4 Ã nAChRs are necessaryand sufficient for both intra-VTA self-administration, as well as nicotine-induced increases in firing of DA neurons (Exley et al. 2011;McGranahan et al. 2011).”
From Mechanisms of Nicotine Addiction (2021) · cites this paper as Exley et al. 2011
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“Nicotine in adolescence is thus poised to alter DA development, as it acts directly on VTA DA neurons through their expression of nAChRs, modulating their firing rate in a population-specific manner in adult rodents [72, 137–139].”
From Adolescent nicotine exposure and persistent neurocircuitry changes: unveiling lifelong psychiatric risks (2025) · cites this paper as [139]
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“However, α4 and α6 subunits are both required for the ability of nicotine to gate DA transmission in the NAc, suggesting that nAChRs in NAc may be more important in motivation to self-administer nicotine (Brunzell et al. 2010;Exley et al. 2011) and that this may affect acquisition of self-administration behavior (Pons et al. 2008;Gotti et al. 2010), as well as nicotine-dependent locomotor activ”
From Mechanisms of Nicotine Addiction (2021) · cites this paper as Exley et al. 2011
In the citing paper
“Varenicline’s interactions with α3β4-, α2-, or α6-containing nAChRs might also contribute to its therapeutic effects given the role of those receptors in both the rewarding and/or aversive effects of nicotine [11, 13, 80, 81].”
From Mechanistic insights into nicotine withdrawal (2011) · cites this paper as [13]
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Metadata
- Authors
- Exley, R., Maubourguet, N., David, V., Eddine, R., Evrard, A., Pons, S., Marti, F., Threlfell, S., Cazala, P., McIntosh, J. M., Changeux, J.-P., Maskos, U., Cragg, S. J., & Faure, P.
- Affiliations
- University of Oxford (GB)
- Centre National de la Recherche Scientifique (FR)
- University of Utah (US)
- Centre National de la Recherche Scientifique, Unité de Recherche Associée 2182, Unité Neurobiologie Intégrative des Systèmes Cholinergiques, Institut Pasteur, 75724 Paris Cedex 15, France;
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-04-18
- Volume
- 108
- Issue
- 18
- Pages
- 7577-7582
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3088627
- OpenAlex
- W1987559996
- Cited by
- 159
- References
- 46
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 5 · 2023: 6 · 2022: 2 · 2021: 3 · 2020: 13 · 2019: 11 · 2018: 8 · 2017: 7 · 2016: 8 · 2015: 13 · 2014: 23 · 2013: 19 · 2012: 19
- FWCI
- 9.47
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Institut national de la recherche scientifique
- Les Laboratories Pierre Fabre
- Parkinson's UK
- European Commission
- Agence Nationale de la Recherche (ANR-09-BLAN-0104)
- Centre National de la Recherche Scientifique
- Fondation Gilbert Lagrue
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Smoking Behavior and Cessation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- nicotinic acetylcholine receptors, nicotine self-administration, nicotine reinforcement, nicotine dependence, ventral tegmental area, dopaminergic neurons, dopamine signaling, nucleus accumbens, neuronal bursting, mesolimbic system
- MeSH terms
- Analysis of Variance, Animals, Autoradiography, Dopamine, Electrophysiology, Genetic Vectors, Mice, Inbred C57BL, Neurons, Nicotine, Receptors, Nicotinic, Lentivirus, Ventral Tegmental Area, Mice, Knockout, Mice
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