Conditioned nicotine withdrawal profoundly decreases the activity of brain reward systems
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Withdrawal from nicotine decreases the activity of brain reward systems, measured in rats by elevations of intracranial self-stimulation (ICSS) thresholds. This reward deficit is hypothesized to contribute to the persistence of the tobacco habit in tobacco smokers. Accumulating evidence suggests that aspects of drug withdrawal may become conditioned to previously neutral environmental stimuli via pavlovian conditioning processes. Here we investigated whether hedonically neutral stimuli repeatedly paired with nicotine withdrawal gained "affective valence" such that withdrawal-associated conditioned stimuli alone decreased brain reward function. Nicotine-dependent rats were presented with a light/tone conditioned stimulus and injected with the nicotinic receptor antagonist dihydro-beta-erythroidine (DHbetaE; 3 mg/kg) for 4 d consecutively; ICSS thresholds were assessed before and immediately after DHbetaE injection. On the test day, the rats were presented with the conditioned stimulus and injected with saline; next, ICSS thresholds were assessed. During conditioning sessions, DHbetaE elevated reward thresholds, and the magnitude by which thresholds were elevated increased during successive conditioning sessions. These data suggest that withdrawal-associated conditioned stimuli potentiated the magnitude of nicotine withdrawal as their motivational significance increased. Most importantly, on the test day, the conditioned stimulus alone elevated reward thresholds. Similarly, in a separate experiment, withdrawal-associated cues elevated reward thresholds in morphine-dependent rats. These data provide the first empirical verification that conditioned nicotine withdrawal may occur after exposure to withdrawal-paired cues. Moreover, these data demonstrate that withdrawal-paired conditioned stimuli attain negative affective valence and can decrease the activity of brain reward systems, mimicking the reward deficit observed during withdrawal from nicotine and other addictive drugs.
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Varenicline's beneficial effects on affect during abstinence are consistent with preclinical evidence for the role of α4β2 nicotinic acetylcholine receptors in nicotine's effect on hedonic state.
“The beneficial effects of varenicline on affect during abstinence are consistent with preclinical evidence for the role of α4β2 nAChRs in nicotine’s effect on hedonic state.”
From Varenicline improves mood and cognition during smoking abstinence (2009) · cites this paper as [39]
Normally neutral stimuli such as a light or tone increase ICSS thresholds if paired with nicotine withdrawal.
“Normally neutral stimuli, such as a light or a tone, will also increase ICSS thresholds if that stimulus is paired with withdrawal from nicotine [183].”
From Mechanistic insights into nicotine withdrawal (2011) · cites this paper as [183]
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- Authors
- Kenny, P. J., & Markou, A.
- Affiliations
- Scripps Research Institute (US)
- Corresponding author
- Markou, Athina
- ORCID
- Kenny, Paul J.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2005-06-29
- Volume
- 25
- Issue
- 26
- Pages
- 6208-6212
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6725046
- OpenAlex
- W2083543186
- Cited by
- 107
- References
- 26
- Citations by year
- 2025: 4 · 2024: 2 · 2022: 5 · 2021: 3 · 2020: 2 · 2019: 3 · 2018: 4 · 2017: 1 · 2016: 3 · 2015: 8 · 2014: 2 · 2013: 4 · 2012: 10
- FWCI
- 3.63
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Tobacco-Related Disease Research Program
- National Institute on Drug Abuse (DA 11946, R56DA011946, R01DA011946)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
- Keywords
- nicotine withdrawal, classical conditioning, brain reward system, intracranial self-stimulation, dihydro-beta-erythroidine, nicotine dependence, morphine dependence, conditioned stimulus
- MeSH terms
- Animals, Brain, Disease Models, Animal, Male, Nicotine, Reward, Substance Withdrawal Syndrome, Rats, Wistar, Substance-Related Disorders, Rats
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