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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Knockout of the α4 subunit abolishes intracerebroventricular self-administration of nicotine.
“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
The Results report that α4-knockout mice did not sustain nicotine self-administration beyond session 3, supporting the loss of sustained self-administration. But the experiment delivered nicotine intracranially into the VTA, not intracerebroventricularly, and the mice showed initial approach behavior rather than an immediate abolition of the response. (LLM, conf=0.90)
Experimental — accuracy not yet measuredIn mice with constitutive α6 knockout, intra-VTA self-administration of nicotine is not disrupted, whereas α4* nAChRs are necessary and sufficient for intra-VTA self-administration and nicotine-induced increases in DA neuron firing.
“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
The Results (page unavailable) show that α6-knockout mice self-administered intra-VTA nicotine similarly to wild-type mice at 100 ng, but less at 10 ng. They also show that α4 deletion prevented sustained self-administration and eliminated nicotine-induced bursting, not all increases in DA-neuron firing rate. Targeted α4 re-expression only partially restored the firing response and did not fully restore long-term self-administration, so the claim that α4* receptors are sufficient for both outcomes overstates the findings. (LLM, conf=0.90)
Experimental — accuracy not yet measuredNicotine in adolescence is poised to alter DA development because it acts directly on VTA DA neurons through their expression of nAChRs, modulating their firing rate in a population-specific manner in adult rodents.
“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]
The Results report that nicotine increased VTA dopamine-neuron firing in mice, with a delayed and attenuated increase in α4-knockout mice. The Discussion links nicotine-induced firing to nAChRs on dopamine cells, but the reported differences are between mouse genotypes, not identified populations of dopamine neurons. The paper does not test adolescent dopamine development; the citing sentence presents that as its own inference. (LLM, conf=0.83)
Experimental — accuracy not yet measuredVarenicline's interactions with α3β4-, α2-, or α6-containing nAChRs might contribute to its therapeutic effects.
“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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- 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 › Physiology › 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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