Addiction‐related neuroadaptations following chronic nicotine exposure
Open accessAbstract
The addiction‐relevant molecular, cellular, and behavioral actions of nicotine are derived from its stimulatory effects on neuronal nicotinic acetylcholine receptors (nAChRs) in the central nervous system. nAChRs expressed by dopamine‐containing neurons in the ventral midbrain, most notably in the ventral tegmental area (VTA), contribute to the reward‐enhancing properties of nicotine that motivate the use of tobacco products. nAChRs are also expressed by neurons in brain circuits that regulate aversion. In particular, nAChRs expressed by neurons in the medial habenula (mHb) and the interpeduncular nucleus (IPn) to which the mHb almost exclusively projects regulate the “set‐point” for nicotine aversion and control nicotine intake. Different nAChR subtypes are expressed in brain reward and aversion circuits and nicotine intake is titrated to maximally engage reward‐enhancing nAChRs while minimizing the recruitment of aversion‐promoting nAChRs. With repeated exposure to nicotine, reward‐ and aversion‐related nAChRs and the brain circuits in which they are expressed undergo adaptations that influence whether tobacco use will transition from occasional to habitual. Genetic variation that influences the sensitivity of addiction‐relevant brain circuits to the actions of nicotine also influence the propensity to develop habitual tobacco use. Here, we review some of the key advances in our understanding of the mechanisms by which nicotine acts on brain reward and aversion circuits and the adaptations that occur in these circuits that may drive addiction to nicotine‐containing tobacco products. image
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By desensitizing nicotine receptors, nicotine can inhibit negative aversive states.
“By desensitizing nicotine receptors, nicotine can inhibit negative aversive states 42 .”
From Substance use disorders: a comprehensive update of classification, epidemiology, neurobiology, clinical aspects, treatment and prevention (2023) · cites this paper as [42]
The Introduction section on nAChR upregulation reports that nicotine desensitizes nicotinic receptors. The section on low-affinity nAChRs reports reduced aversive responses when certain receptor subunits are deficient. Neither passage establishes that nicotine inhibits aversive states by desensitizing those receptors; the claimed mechanism is unsupported. (LLM, conf=0.82)
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- Authors
- Wills, L., & Kenny, P. J.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Kenny, Paul J.
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2021-06
- Volume
- 157
- Issue
- 5
- Pages
- 1652-1673
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- PMC
- PMC13249106
- OpenAlex
- W3137382578
- Cited by
- 61
- References
- 333
- Citations by year
- 2026: 10 · 2025: 6 · 2024: 14 · 2023: 18 · 2022: 7 · 2021: 6
- FWCI
- 1.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- Funders
- National Institute on Drug Abuse (DA020686, DA045649)
- 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 dependence, nicotine aversion, nicotinic acetylcholine receptors, ventral tegmental area, medial habenula, interpeduncular nucleus, nicotine reward, neural adaptation
- MeSH terms
- Adaptation, Physiological, Animals, Dopamine, Humans, Nicotine, Receptors, Nicotinic, Reward, Tobacco Use Disorder
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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