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Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors
Abstract
Worldwide, 100 million people are expected to die this century from the consequences of nicotine addiction, but nicotine is also known to enhance cognitive performance. Identifying the molecular mechanisms involved in nicotine reinforcement and cognition is a priority and requires the development of new in vivo experimental paradigms. The ventral tegmental area (VTA) of the midbrain is thought to mediate the reinforcement properties of many drugs of abuse. Here we specifically re-expressed the beta2-subunit of the nicotinic acetylcholine receptor (nAChR) by stereotaxically injecting a lentiviral vector into the VTA of mice carrying beta2-subunit deletions. We demonstrate the efficient re-expression of electrophysiologically responsive, ligand-binding nicotinic acetylcholine receptors in dopamine-containing neurons of the VTA, together with the recovery of nicotine-elicited dopamine release and nicotine self-administration. We also quantified exploratory behaviours of the mice, and showed that beta2-subunit re-expression restored slow exploratory behaviour (a measure of cognitive function) to wild-type levels, but did not affect fast navigation behaviour. We thus demonstrate the sufficient role of the VTA in both nicotine reinforcement and endogenous cholinergic regulation of cognitive functions.
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In the citing paper
“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 Maskos et al. 2005
In the citing paper
“ACh provides a complex regulation of reward and motivation behaviors through its actions on dopamine (DA) circuitry [68–72].”
From Adolescent nicotine exposure and persistent neurocircuitry changes: unveiling lifelong psychiatric risks (2025) · cites this paper as [72]
In the citing paper
“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 [72]
In the citing paper
“Evidence for this idea stemmed from studies showing that mice lacking the ␣4, ␣6, and/or 2 nAChR subunits fail to self-administer nicotine, whereas re-expression of these subunits in the ventral tegmental area of knockout mice restored nicotine self-administration”
From Varenicline Is a Potent Partial Agonist at α6β2* Nicotinic Acetylcholine Receptors in Rat and Monkey Striatum (2012) · cites this paper as Maskos et al., 2005
In the citing paper
“extensive studies showing that 2, ␣4, or ␣6 nAChRs knockout mice fail to self-administer nicotine (Picciotto et al., 1998;Marubio et al., 2003;Maskos et al., 2005;Pons et al., 2008).”
From Varenicline Is a Potent Partial Agonist at α6β2* Nicotinic Acetylcholine Receptors in Rat and Monkey Striatum (2012) · cites this paper as Maskos et al., 2005
In the citing paper
“particularly because the addictive effects of nicotine are mediated primarily through stimulation of nAChRs in the VTA (Drenan et al., 2008; Maskos et al., 2005; McGranahan et al., 2011; Picciotto et al., 1998).”
From Acetylcholine as a Neuromodulator: Cholinergic Signaling Shapes Nervous System Function and Behavior (2012) · cites this paper as Maskos et al., 2005
In the citing paper
“Mice learn to run on a Y-maze to self-administer nicotine into the VTA, an effect that can be diminished by systemic administration of dopamine antagonists”
From Dopamine reward circuitry: Two projection systems from the ventral midbrain to the nucleus accumbens–olfactory tubercle complex (2007) · cites this paper as Maskos et al., 2005
In the citing paper
“Nicotine reinforcement and reward is mediated through nAChRs in the mesolimbic system (Maskos et al., 2005; McGranahan et al., 2011; Tolu et al., 2012)”
From Mood and anxiety regulation by nicotinic acetylcholine receptors: A potential pathway to modulate aggression and related behavioral states (2015) · cites this paper as Maskos et al., 2005
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Metadata
- Authors
- Maskos, U., Molles, B. E., Pons, S., Besson, M., Guiard, B. P., Guilloux, J.-P., Evrard, A., Cazala, P., Cormier, A., Mameli-Engvall, M., Dufour, N., Cloëz-Tayarani, I., Bemelmans, A.-P., Mallet, J., Gardier, A. M., David, V., Faure, P., Granon, S., & Changeux, J.-P.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Université Paris-Sud (FR)
- Corresponding author
- Changeux, J.-P.
- ORCID
- Venue
- Nature
- Published
- 2005-07
- Volume
- 436
- Issue
- 7047
- Pages
- 103-107
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2141456252
- Cited by
- 566
- References
- 32
- Citations by year
- 2026: 7 · 2025: 19 · 2024: 7 · 2023: 18 · 2022: 10 · 2021: 18 · 2020: 21 · 2019: 17 · 2018: 21 · 2017: 17 · 2016: 15 · 2015: 26 · 2014: 32 · 2013: 34 · 2012: 32
- FWCI
- 18.32
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- 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
- nicotine, nicotinic acetylcholine receptors, beta2 subunit, ventral tegmental area, dopaminergic neurons, nicotine self-administration, nicotine reinforcement, nicotine dependence, cognitive function, exploratory behavior, lentiviral vectors, cholinergic modulation, dopamine release
- MeSH terms
- Animals, Cognition, Dopamine, Exploratory Behavior, Locomotion, Morphine, Neurons, Nicotine, Receptors, Nicotinic, Gene Expression, Ventral Tegmental Area, Receptors, Adrenergic, beta-2, Mice
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