Molecular Mechanism for a Gateway Drug: Epigenetic Changes Initiated by Nicotine Prime Gene Expression by Cocaine
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The finding that nicotine enhances the brain’s response to cocaine may explain how smoking acts as a gateway drug for this addictive stimulant.
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Acute and chronic drug exposures (stimulants, opioids, alcohol, nicotine) increase total cellular levels of acetylation of histones H3 and H4, apparently by unbalancing HAT and HDAC function.
“These studies have shown that acute and chronic drug exposures (stimulants, opioids, alcohol, nicotine) increase total cellular levels of acetylation of histones H3 and H4 105- 110 , apparently by unbalancing HAT and HDAC function.”
From Substance use disorders: a comprehensive update of classification, epidemiology, neurobiology, clinical aspects, treatment and prevention (2023) · cites this paper as [109]
The Results sections on seven-day nicotine treatment report increased H3 and H4 acetylation across the mouse striatum and suggest that reduced HDAC activity explains the increase. This paper does not establish the same effect for acute exposures, opioids, or alcohol; it reports no increase in striatal H3 or H4 acetylation after seven days of cocaine. Page numbers were not supplied in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measuredThese studies were performed in adult mice.
“Although such findings demonstrate epigenetic mechanisms that could mediate nicotine ‘gateway’ effects, these studies were performed in adult mice.”
From <scp>N</scp> icotine and the adolescent brain (2015) · cites this paper as Levine et al. 2011
The Results section on chronic nicotine pretreatment says the experiments used C57BL/6J mice, and the section on hypoacetylated chromatin also describes experiments in mice. Our copy does not specify the mice’s ages, so it supports the species but not the claim that they were adults (searched: adult, age in weeks, adolescent). No page numbers are available in the indexed passages. (LLM, conf=0.78)
Experimental — accuracy not yet measuredChronic nicotine exposure sensitizes cocaine behavioral responses and long-term potentiation in the nucleus accumbens, amygdala, and hippocampus.
“A series of studies investigating the ‘gateway’ effect of nicotine also found that chronic nicotine exposure sensitizes cocaine behavioral responses and long-term potentiation in the nucleus accumbens, amygdala, and hippocampus (Levine et al. 2011; Huang et al. 2013, 2014).”
From <scp>N</scp> icotine and the adolescent brain (2015) · cites this paper as Levine et al. 2011
The Results sections on behavioral responses and LTP report that seven days of nicotine exposure enhanced mice’s behavioral responses to cocaine and enhanced cocaine-induced reduction of LTP in the nucleus accumbens (page numbers unavailable). They do not establish LTP effects in the amygdala or hippocampus; if “sensitizes long-term potentiation” implies increased LTP, the reported effect is in the opposite direction. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAt the molecular level, nicotine exerts a priming effect by enhancing cocaine's ability to induce FosB, a key mediator of addiction.
“At the molecular level, nicotine exerts a priming effect by enhancing the ability of cocaine to induce FosB, a key mediator of addiction.”
From Developmental toxicity of nicotine: A transdisciplinary synthesis and implications for emerging tobacco products (2017) · cites this paper as [305]
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- Authors
- Levine, A., Huang, Y., Drisaldi, B., Griffin, E. A., Pollak, D. D., Xu, S., Yin, D., Schaffran, C., Kandel, D. B., & Kandel, E. R.
- Affiliations
- New York State Psychiatric Institute (US)
- Department of Neuroscience, College of Physicians and Surgeons, Columbia University, 1051 Riverside Drive, New York, NY 10032, USA.
- Columbia University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Levine, Amir
- Pollak, Daniela D.
- Kandel, Denise B.
- Kandel, Eric R.
- ORCID
- Venue
- Science Translational Medicine
- Published
- 2011-11-02
- Volume
- 3
- Issue
- 107
- Pages
- 107ra109-107ra109
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- PMC
- PMC4042673
- OpenAlex
- W2103610088
- Cited by
- 280
- References
- 33
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 7 · 2023: 15 · 2022: 16 · 2021: 17 · 2020: 41 · 2019: 26 · 2018: 16 · 2017: 24 · 2016: 18 · 2015: 19 · 2014: 23 · 2013: 27 · 2012: 16
- FWCI
- 9.00
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (T32MH015144)
- National Institute on Drug Abuse (K-5 DA00081, K05DA000081, R01DA024001)
- 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
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- gateway drugs, nicotine, cocaine, histone deacetylase inhibition, histone acetylation, FosB, long-term potentiation, synaptic plasticity, striatum, nucleus accumbens, locomotor sensitization, conditioned place preference, cocaine dependence, smoking, theophylline
- MeSH terms
- Animals, Cocaine, Histone Deacetylases, Humans, Mice, Inbred C57BL, Nicotine, Theophylline, Cocaine-Related Disorders, Epigenesis, Genetic, Mice, Histone Deacetylase Inhibitors
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