The Role of Cystine-Glutamate Exchange in Nicotine Dependence in Rats and Humans
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Background The present study determined if, akin to cocaine, nicotine self-administration in rats induces adaptations in the expression of glutamate transporters and cystine-glutamate exchangers in brain nuclei implicated in reinforcement and if treating cigarette smokers with a drug that restores cystine-glutamate exchange affects the number of cigarettes smoked.Methods Rats self-administered nicotine intravenously for 12 hours/day or received nicotine through osmotic minipumps for 21 days. Somatic signs of withdrawal were measured and immunoblotting was performed 12 hours after the last nicotine exposure to determine if the catalytic subunit of the cystine-glutamate exchanger, xCT, or the glial glutamate transporter, GLT-1, were altered in the ventral tegmental area (VTA), nucleus accumbens, prefrontal cortex, or amygdala. For the smoking reduction study in humans, nicotine-dependent smokers were treated for 4 weeks with N-acetylcysteine (2400 mg daily) to promote cystine-glutamate exchange or placebo. Participants provided weekly ratings of withdrawal symptoms, craving, and carbon monoxide (CO) measurements and logged daily cigarette and alcohol use.Results Rats receiving nicotine via self-administration or minipumps displayed somatic signs of withdrawal, but only nicotine self-administering rats showed decreased xCT expression in the nucleus accumbens and VTA and decreased GLT-1 expression in the nucleus accumbens. Human smokers treated with N-acetylcysteine reported a reduction in cigarettes smoked, and there was no effect of N-acetylcysteine on estimates of CO levels, craving, or withdrawal.Conclusions These results indicate that the cystine-glutamate exchanger and the glial glutamate transporter are downregulated after nicotine self-administration, and augmenting exchanger activity with N-acetylcysteine reduced the number of cigarettes smoked in nicotine-dependent individuals.
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A first small placebo-controlled study with 29 nicotine-dependent patients using 2.4 g/day NAC found no significant differences in exhaled carbon monoxide or daily cigarette use between NAC and placebo.
“A first small placebo-controlled study with 29 nicotine-dependent patients used 2.4 g/day of NAC as a treatment for tobacco cessation.There were no significant differences in exhaled carbon monoxide (CO EXH ) levels between patients treated with NAC and placebo, and no significant difference between NAC and placebo treatment in the daily use of cigarettes.14”
From <i>N</i>-acetylcysteine for therapy-resistant tobacco use disorder: a pilot study (2015) · cites this paper as [14]
The two prior studies provide inconsistent evidence that NAC may have some efficacy in treating tobacco use disorder.
“All in all, these two studies provide inconsistent evidence that NAC may have some efficacy in the treatment of tobacco use disorder.”
From <i>N</i>-acetylcysteine for therapy-resistant tobacco use disorder: a pilot study (2015) · cites this paper as [14]
Nicotine self-administration decreases xCT in the NAcc and VTA and GLT-1 in the NAcc.
“Nicotine self-administration also decreases expression of the cystine-glutamate exchanger, xCT, in the NAcc and VTA, and decreases the glial glutamate transporter, GLT-1, in the NAcc [102].”
From Mechanistic insights into nicotine withdrawal (2011) · cites this paper as [102]
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References 21 · Cited by 260
Research works printed but not linked: 1
- [22]Zhou W Kalivas PW 2008 N-acetylcysteine reduces extinction responding and induces enduring reductions in cue- and heroin-induced drug-seeking Biol Psychiatry 63 338 340 17719565 PMC2709691
- Authors
- Knackstedt, L. A., LaRowe, S., Mardikian, P., Malcolm, R., Upadhyaya, H., Hedden, S., Markou, A., & Kalivas, P. W.
- Affiliations
- Medical University of South Carolina (US)
- University of California San Diego (US)
- Corresponding author
- Kalivas, Peter W.
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2009-05
- Volume
- 65
- Issue
- 10
- Pages
- 841-845
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC2756612
- OpenAlex
- W2088991430
- Cited by
- 260
- References
- 21
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 10 · 2023: 10 · 2022: 10 · 2021: 12 · 2020: 21 · 2019: 15 · 2018: 16 · 2017: 17 · 2016: 18 · 2015: 20 · 2014: 18 · 2013: 16 · 2012: 16
- FWCI
- 10.24
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Drug Abuse (R37DA003906, R01DA1194, R56DA011946, R01DA012513, P50DA015369, R01DA003906, R01DA011946, R21DA026010)
- Topics
- Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- nicotine dependence, cystine/glutamate exchanger, SLC7A11, glutamate transporter GLT-1, N-acetylcysteine, nicotine self-administration, nicotine withdrawal, nucleus accumbens, ventral tegmental area, glutamate homeostasis, smoking reduction, craving, cigarette smoking
- MeSH terms
- Acetylcysteine, Amygdala, Animals, Brain, Carbon Monoxide, Female, Humans, Male, Middle Aged, Nicotine, Nucleus Accumbens, Pilot Projects, Self Administration, Substance Withdrawal Syndrome, Tobacco Use Disorder, Rats, Wistar, Prefrontal Cortex, Ventral Tegmental Area, Amino Acid Transport System y+, Excitatory Amino Acid Transporter 2, Rats
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