Cholinergic modulation of dopaminergic reward areas: upstream and downstream targets of nicotine addiction
Abstract
Nicotine reinforces smoking behaviour by activating nicotinic acetylcholine receptors in the midbrain dopaminergic reward centres. Upstream of the dopaminergic neurons nicotine induces long-term potentiation of the excitatory input to dopamine cells in the ventral tegmental area, and depresses inhibitory inputs. Both effects of nicotine were shown to last much longer than the nicotine exposure and together will activate the dopaminergic ventral tegmental area projection toward the nucleus accumbens. However, downstream of dopamine, effects of nicotine are also likely to occur. Cholinergic interneurons within the nucleus accumbens are important in the tonic control of the gamma-amino buteric acid (GABA) nucleus accumbens output neurons, which project back to the ventral tegmental area. The nicotinic acetylcholine receptors that mediate this control are likely to desensitise upon preexposure to the nicotine concentrations found in the blood of smokers. Thus, synaptic mechanisms both upstream and downstream of dopamine release are potentially important factors contributing to the etiology of nicotine addiction.
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ACh provides complex regulation of reward and motivation behaviors through its actions on dopamine circuitry.
“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 [69]
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“Nicotine also has indirect or circuit effects on DA neurotransmission, as nAChRs are also present on DA axon terminals, on neurons present in dopaminoceptive regions, and importantly on VTA GABA neurons, which regulate DA neuron activity [52, 68, 69, 140].”
- Authors
- Mansvelder, H. D., De Rover, M., McGehee, D. S., & Brussaard, A. B.
- Affiliations
- Vrije Universiteit Amsterdam (NL)
- University of Chicago (US)
- Corresponding author
- Brussaard, Arjen B.
- Venue
- European Journal of Pharmacology
- Publisher
- Elsevier BV
- Published
- 2003-11
- Volume
- 480
- Issue
- 1-3
- Pages
- 117-123
- ISSN
- 0014-2999 (ISSN-L)
- OpenAlex
- W2062697629
- Cited by
- 130
- References
- 46
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 4 · 2020: 7 · 2019: 5 · 2018: 4 · 2016: 8 · 2015: 4 · 2014: 4 · 2013: 8 · 2012: 4
- FWCI
- 0.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- VU Research Portal (publishedVersion)
- Digital Academic REpository of VU University Amsterdam (Vrije Universiteit Amsterdam) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Topics
- 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
- Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
- Keywords
- nicotine dependence, nicotinic acetylcholine receptors, cholinergic modulation, dopaminergic reward, ventral tegmental area, nucleus accumbens, long-term potentiation, GABAergic interneurons, synaptic plasticity, smoking behavior
- MeSH terms
- Animals, Cholinergic Fibers, Dopamine, Humans, Interneurons, Nicotine, Receptors, Nicotinic, Reward, Substance-Related Disorders
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