Crucial role of α4 and α6 nicotinic acetylcholine receptor subunits from ventral tegmental area in systemic nicotine self-administration
Open accessAbstract
The identification of the molecular mechanisms involved in nicotine addiction and its cognitive consequences is a worldwide priority for public health. Novel in vivo paradigms were developed to match this aim. Although the beta2 subunit of the neuronal nicotinic acetylcholine receptor (nAChR) has been shown to play a crucial role in mediating the reinforcement properties of nicotine, little is known about the contribution of the different alpha subunit partners of beta2 (i.e., alpha4 and alpha6), the homo-pentameric alpha7, and the brain areas other than the ventral tegmental area (VTA) involved in nicotine reinforcement. In this study, nicotine (8.7-52.6 microg free base/kg/inf) self-administration was investigated with drug-naive mice deleted (KO) for the beta2, alpha4, alpha6 and alpha7 subunit genes, their wild-type (WT) controls, and KO mice in which the corresponding nAChR subunit was selectively re-expressed using a lentiviral vector (VEC mice). We show that WT mice, beta2-VEC mice with the beta2 subunit re-expressed exclusively in the VTA, alpha4-VEC mice with selective alpha4 re-expression in the VTA, alpha6-VEC mice with selective alpha6 re-expression in the VTA, and alpha7-KO mice promptly self-administer nicotine intravenously, whereas beta2-KO, beta2-VEC in the substantia nigra, alpha4-KO and alpha6-KO mice do not respond to nicotine. We thus define the necessary and sufficient role of alpha4beta2- and alpha6beta2-subunit containing nicotinic receptors (alpha4beta2*- and alpha6beta2*-nAChRs), but not alpha7*-nAChRs, present in cell bodies of the VTA, and their axons, for systemic nicotine reinforcement in drug-naive mice.
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α4 and α6 subunits are both required for nicotine to gate DA transmission in the NAc, suggesting that nAChRs in the NAc may be more important in motivation to self-administer nicotine and may affect acquisition of self-administration and nicotine-dependent locomotor activation.
“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 Pons et al. 2008
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Experimental — accuracy not yet measuredMice lacking the α6 subunit do not acquire nicotine self-administration.
“Mice lacking the α6 subunit do not acquire nicotine self-administration (Pons et al. 2008).”
From Mechanisms of Nicotine Addiction (2021) · cites this paper as Pons et al. 2008
Knockout of the α7 subunit in mice does not affect nicotine place preference or acquisition of nicotine self-administration.
“Despite its contribution to nicotine-dependent plasticity in the VTA, knockout of the α7 subunit in mice does not affect nicotine place preference (Walters et al. 2006) or acquisition of nicotine self-administration (Pons et al. 2008).”
From Mechanisms of Nicotine Addiction (2021) · cites this paper as Pons et al. 2008
Selective viral reexpression of β2* or α4* nAChRs in the VTA is sufficient to support intra-VTA and systemic nicotine self-administration, identifying subtypes necessary for nicotine reinforcement and showing the importance of nAChRs within the VTA.
“Selective viral reexpression of β2 Ã (Maskos et al. 2005;Pons et al. 2008) or α4 Ã nAChRs in the VTA is sufficient to support both intra-VTA (Maskos et al. 2005) and systemic nicotine self-administration (Pons et al. 2008), identifying the nAChR subtypes necessary for nicotine reinforcement, as well as showing the importance of nAChRs within the VTA itself for this behavior.”
From Mechanisms of Nicotine Addiction (2021) · cites this paper as Pons et al. 2008
A smaller population of α6β2* nAChRs is restricted to CNS catecholaminergic neurons, including nigrostriatal neurons, and may be involved in reward, addiction, and motor activity.
“There is also a smaller population of ␣62* nAChRs, which is restricted in localization to CNS catecholaminergic neurons, including those in the nigrostriatal pathway, which may be involved in reward, addiction, and motor activity (Drenan et al., 2008;Pons et al., 2008).”
From Nicotinic receptor-mediated reduction in l-DOPA-induced dyskinesias may occur via desensitization (2010) · cites this paper as Pons et al., 2008
Nicotine binds to nicotinic acetylcholine receptors in many parts of the brain, particularly the ventral tegmental area.
“The nicotine binds to nicotinic acetylcholine receptors in many parts of the brain but of particular interest is the ventral tegmental area (7,8).”
From The Multiple Facets of Cigarette Addiction and What They Mean for Encouraging and Helping Smokers to Stop (2009) · cites this paper as [8]
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References 89 · Cited by 312
- Authors
- Pons, S., Fattore, L., Cossu, G., Tolu, S., Porcu, E., McIntosh, J. M., Changeux, J. P., Maskos, U., & Fratta, W.
- Affiliations
- Institut Pasteur (FR)
- University of Cagliari (IT)
- Centre National de la Recherche Scientifique (FR)
- University of Utah (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2008-11-19
- Volume
- 28
- Issue
- 47
- Pages
- 12318-12327
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2819191
- OpenAlex
- W1978262730
- Cited by
- 312
- References
- 89
- Citations by year
- 2025: 5 · 2024: 6 · 2023: 14 · 2022: 4 · 2021: 12 · 2020: 15 · 2019: 14 · 2018: 15 · 2017: 17 · 2016: 17 · 2015: 24 · 2014: 30 · 2013: 29 · 2012: 26
- FWCI
- 11.67
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- UNICA IRIS Institutional Research Information System (University of Cagliari) (submittedVersion)
- Funders
- European Commission
- Agence Nationale de la Recherche (ANR-06-NEUR-0038)
- Centre National de la Recherche Scientifique
- Institut National Du Cancer
- National Institutes of Health (GM 48677)
- National Institute of Mental Health (MH53631, R01MH053631, R29MH053631)
- National Institute on Drug Abuse (R01DA012242, DA12242)
- National Institute of General Medical Sciences (P01GM048677, GM48677)
- 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, alpha4 subunit, alpha6 subunit, beta2 subunit, alpha7 subunit, ventral tegmental area, nicotine dependence, nicotine reinforcement, knockout mice, substantia nigra
- MeSH terms
- Analysis of Variance, Animals, Autoradiography, Behavior, Animal, Calcium Channel Blockers, Conditioning, Operant, Dose-Response Relationship, Drug, Exploratory Behavior, Iodine Isotopes, Male, Mice, Inbred C57BL, Nicotine, Receptors, Nicotinic, Self Administration, Ventral Tegmental Area, Mice, Knockout, Nicotinic Agonists, Conotoxins, Mice, alpha7 Nicotinic Acetylcholine Receptor
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