The neurobiology of tobacco dependence: A preclinical perspective on the role of the dopamine projections to the nucleus
Abstract
It is now widely accepted that nicotine is the primary addictive component of tobacco smoke and that a majority of habitual smokers find it difficult to quit smoking because of their dependence upon this component of the smoke. However, although nicotine replacement therapy elicits a clinically valuable and significant improvement in the number of quit attempts that are ultimately successful, its efficacy remains disappointingly low. This review considers some of the reasons for this problem. It focuses on the hypothesis that stimulation of the dopamine (DA) projections to the medial shell and the core of the nucleus accumbens play complementary roles in the development of nicotine dependence. The hypothesis proposes that increased extra-synaptic DA in the medial shell of the accumbens confers hedonic properties on behaviors, such as smoking, which deliver nicotine, and thereby increase the probability that the response is learned. It also summarizes the evidence that the primary role of the increased DA overflow, observed in the accumbal core of nicotine-pretreated individuals, challenged with nicotine, is the attribution of incentive salience to cues associated with delivery of the drug and the transition to Pavlovian responding to these conditioned stimuli. The review argues that sensitization of the DA projections to the accumbal core, and the behaviors that depend upon this process, play a pivotal role in the maintenance of the tobacco smoking habit and that it is this component of the dependence that is inadequately addressed by nicotine replacement therapy.
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Dopamine release in the core of the nucleus accumbens appears to act to generate stimulus-impulse associations.
“Dopamine release in the core appears to act to generate stimulus-impulse associations (10,11).”
From The Multiple Facets of Cigarette Addiction and What They Mean for Encouraging and Helping Smokers to Stop (2009) · cites this paper as [11]
The binding of nicotine to receptors in the ventral tegmental area results in pleasant sensations because of dopamine release in the nucleus accumbens shell.
“The binding of nicotine to receptors in the ventral tegmental area (VTA), aside from generating the impulse to smoke by virtue of dopamine release in the core of the nucleus accumbens, results in pleasant sensations because of dopamine release in the nucleus accumbens shell (11).”
From The Multiple Facets of Cigarette Addiction and What They Mean for Encouraging and Helping Smokers to Stop (2009) · cites this paper as [11]
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Jimenez-Ruiz, C. A., Miranda, J. A. R., Pinedo, Á. R., Ferrero, M. B., Reina, S. S., Orive, J. I. D. G., Guzmán, J. G., Casado, L. R., Trullén, A. P., & Fagerström, K. O. (2008) · Archivos de Bronconeumología · doi:10.1016/s1579-2129(09)60018-5 · Cited by 33 · see citing works
Electronic cigarettes for smoking cessation
Lindson, N., Livingstone‐Banks, J., Butler, A. R., McRobbie, H. J., Bullen, C., Hájek, P., Wu, A. D., Begh, R. A., Theodoulou, A., Notley, C. J., et al. (2025) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd010216.pub10 · Cited by 35 · see citing works
Peckham, E. J., Man, M., Mitchell, N., Li, J., Becque, T., Knowles, S. E., Bradshaw, T., Planner, C., Parrott, S., Michie, S., et al. (2015) · Health Technology Assessment · doi:10.3310/hta19250 · Cited by 31 · see citing works
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- Authors
- Balfour, D.
- Affiliations
- University of Dundee (GB)
- Corresponding author
- Balfour, David
- ORCID
- Balfour, David
- Venue
- Nicotine & Tobacco Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2004-12-01
- Volume
- 6
- Issue
- 6
- Pages
- 899-912
- ISSN
- 1462-2203 (ISSN-L)
- 1469-994X
- OpenAlex
- W2322700613
- Cited by
- 251
- References
- 2
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 6 · 2023: 5 · 2022: 3 · 2021: 7 · 2020: 4 · 2019: 5 · 2018: 5 · 2017: 12 · 2016: 12 · 2015: 9 · 2014: 14 · 2013: 17 · 2012: 15
- FWCI
- 11.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nicotine & Tobacco Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- Topics
- Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- nicotine dependence, smoking, nucleus accumbens, incentive salience, classical conditioning, nicotine replacement therapy, smoking cessation, hedonic behavior, dopamine sensitization
- MeSH terms
- Conditioning, Classical, Dopamine, Drug Administration Routes, Humans, Neurons, Nicotine, Nucleus Accumbens, Psychological Theory, Synapses, Tobacco Use Disorder, Smoking Cessation
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