Chronic nicotine administration decreases the functioning of the cystine–glutamate antiporter system xc− which is hypothesized to promote nicotine-taking and nicotine-seeking behaviors. N-acetylcysteine (NAC), a cystine pro-drug, increases the activity of the cystine–glutamate antiporter system xc−. Thus, NAC could potentially reverse nicotine-induced alterations in glutamatergic transmission and decrease nicotine taking and seeking.
Objectives and methods
To test this hypothesis in the present study, the effects of acute NAC treatment (30, 60, and 90 mg/kg, i.p.) on nicotine (fixed- and progressive-ratio schedules) and food (fixed-ratio schedule) self-administration were assessed in rats. In addition, the effects of acute NAC treatment on cue-induced reinstatement of nicotine- and food-seeking behaviors were investigated. Finally, the effects of repeated daily NAC administration (60 mg/kg, i.p., 14 days) on nicotine and food self-administration were assessed.
Acute NAC administration decreased nicotine self-administration but not food responding under a fixed-ratio schedule of reinforcement. In addition, acute NAC administration showed a nonsignificant trend in attenuating nicotine self-administration under a progressive-ratio schedule that was similar to the dose–response function under the fixed-ratio schedule. Furthermore, repeated NAC administration decreased nicotine self-administration from day 6 to 14 compared with vehicle treatment, with no indication of tolerance development. By contrast, repeated NAC administration decreased food responding from day 6 to 8 compared with vehicle treatment and showed rapid development of tolerance. Finally, acute NAC administration attenuated cue-induced reinstatement of nicotine and food seeking.
Altogether, these findings suggest that NAC may be useful in promoting smoking cessation in humans.
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Amen SL, Piacentine LB, Ahmad ME, Li SJ, Mantsch JR, Risinger RC, Baker DA (2011) Repeated N-acetyl cysteine reduces cocaine seeking in rodents and craving in cocaine-dependent humans. Neuropsychopharmacology 36:871–878
Baker DA, McFarland K, Lake RW, Shen H, Tang XC, Toda S, Kalivas PW (2003) Neuroadaptations in cystine-glutamate exchange underlie cocaine relapse. Nat Neurosci 6:743–749
Bell K, Duffy P, Kalivas PW (2000) Context-specific enhancement of glutamate transmission by cocaine. Neuropsychopharmacology 23:335–344
Bespalov AY, Dravolina OA, Sukhanov I, Zakharova E, Blokhina E, Zvartau E, Danysz W, van Heeke G, Markou A (2005) Metabotropic glutamate receptor (mGluR5) antagonist MPEP attenuated cue- and schedule-induced reinstatement of nicotine self-administration behavior in rats. Neuropharmacology 49(Suppl 1):167–178
Bossert JM, Poles GC, Sheffler-Collins SI, Ghitza UE (2006) The mGluR2/3 agonist LY379268 attenuates context- and discrete cue-induced reinstatement of sucrose seeking but not sucrose self-administration in rats. Behav Brain Res 173:148–152
D'Souza MS, Liechti ME, Ramirez-Niño AM, Kuczenski R, Markou A (2011) The metabotropic glutamate 2/3 receptor agonist LY379268 blocked nicotine-induced increases in nucleus accumbens shell dopamine only in the presence of a nicotine-associated context in rats. Neuropsychopharmacology 36:2111–2124
Friedman GD, Siegelaub AB (1980) Changes after quitting cigarette smoking. Circulation 61:716–723
Grant JE, Kim SW, Odlaug BL (2007) N-acetyl cysteine, a glutamate-modulating agent, in the treatment of pathological gambling: a pilot study. Biol Psychiatry 62:652–657
Griffith OW (1999) Biologic and pharmacologic regulation of mammalian glutathione synthesis. Free Radic Biol Med 27:922–935
Hotsenpiller G, Giorgetti M, Wolf ME (2001) Alterations in behaviour and glutamate transmission following presentation of stimuli previously associated with cocaine exposure. Eur J Neurosci 14:1843–1855
Kalivas PW (2009) The glutamate homeostasis hypothesis of addiction. Nat Rev Neurosci 10:561–572
Kau KS, Madayag A, Mantsch JR, Grier MD, Abdulhameed O, Baker DA (2008) Blunted cystine–glutamate antiporter function in the nucleus accumbens promotes cocaine-induced drug seeking. Neuroscience 155:530–537
Knackstedt LA, LaRowe S, Mardikian P, Malcolm R, Upadhyaya H, Hedden S, Markou A, Kalivas PW (2009) The role of cystine–glutamate exchange in nicotine dependence in rats and humans. Biol Psychiatry 65:841–845
Knackstedt LA, Melendez RI, Kalivas PW (2010) Ceftriaxone restores glutamate homeostasis and prevents relapse to cocaine seeking. Biol Psychiatry 67:81–84
Kenny PJ, Markou A (2004) The ups and downs of addiction: role of metabotropic glutamate receptors. Trends Pharmacol Sci 25:265–272
Kenny PJ, Chartoff E, Roberto M, Carlezon WA Jr, Markou A (2009) NMDA receptors regulate nicotine-enhanced brain reward function and intravenous nicotine self-administration: role of the ventral tegmental area and central nucleus of the amygdala. Neuropsychopharmacology 34:266–281
Kupchik YM, Moussawi K, Tang XC, Wang X, Kalivas BC, Kolokithas R, Ogburn KB, Kalivas PW (2012) The effect of N-acetylcysteine in the nucleus accumbens on neurotransmission and relapse to cocaine. Biol Psychiatry 71(11):978–986. doi:10.1016/j.biopsych.2011.10.024
LaRowe SD, Mardikian P, Malcolm R, Myrick H, Kalivas P, McFarland K, Saladin M, McRae A, Brady K (2006) Safety and tolerability of N-acetylcysteine in cocaine-dependent individuals. Am J Addict 15:105–110
Liechti ME, Lhuillier L, Kaupmann K, Markou A (2007) Metabotropic glutamate 2/3 receptors in the ventral tegmental area and the nucleus accumbens shell are involved in behaviors relating to nicotine dependence. J Neurosci 27:9077–9085
Liechti ME, Markou A (2008) Role of the glutamatergic system in nicotine dependence: implications for the discovery and development of new pharmacological smoking cessation therapies. CNS Drugs 22:705–724
Lo M, Wang YZ, Gout PW (2008) The xc− cystine/glutamate antiporter: a potential target for therapy of cancer and other diseases. J Cell Physiol 215:593–602
Madayag A, Lobner D, Kau KS, Mantsch JR, Abdulhameed O, Hearing M, Grier MD, Baker DA (2007) Repeated N-acetylcysteine administration alters plasticity-dependent effects of cocaine. J Neurosci 27:13968–13976
Markou A (2008) Neurobiology of nicotine dependence. Philos Trans R Soc Lond B Biol Sci 363:3159–3168
Meister A (1985) Methods for the selective modification of glutathione metabolism and study of glutathione transport. Methods Enzymol 113:571–585
Moussawi K, Kalivas PW (2010) Group II metabotropic glutamate receptors (mGlu2/3) in drug addiction. Eur J Pharmacol 639:115–122
Moussawi K, Zhou W, Shen H, Reichel CM, See RE, Carr DB, Kalivas PW (2011) Reversing cocaine-induced synaptic potentiation provides enduring protection from relapse. Proc Natl Acad Sci 108:385–390
Murray JE, Everitt BJ, Belin D (2012) N-Acetylcysteine reduces early- and late-stage cocaine seeking without affecting cocaine taking in rats. Addict Biol 17(2):437–440. doi:10.1111/j.1369-1600.2011.00330.x
Olsson B, Johansson M, Gabrielsson J, Bolme P (1988) Pharmacokinetics and bioavailability of reduced and oxidized N-acetylcysteine. Eur J Clin Pharmacol 34:77–82
Paterson NE, Semenova S, Gasparini F, Markou A (2003) The mGluR5 antagonist MPEP decreased nicotine self-administration in rats and mice. Psychopharmacology (Berlin) 167:257–264
Paterson NE, Froestl W, Markou A (2004) The GABA(B) receptor agonists baclofen and CGP44532 decreased nicotine self- administration in the rat. Psychopharmacology 172:179–186
Reichel CM, Moussawi K, Do PH, Kalivas PW, See RE (2011) Chronic N-acetylcysteine during abstinence or extinction following cocaine self-administration produces enduring reductions in drug seeking. J Pharmacol Exp Ther 337:487–493
Sanger DJ, Blackman DE (1976) Rate-dependent effects of drugs: a review of the literature. Pharmacol Biochem Behav 4:73–83
Schmaal L, Berk L, Hulstijn KP, Cousijn J, Wiers RW, van den Brink W (2011) Efficacy of N-acetylcysteine in the treatment of nicotine dependence: a double-blind placebo-controlled pilot study. Eur Addict Res 17:211–216
Shiffman S, Brockwell SE, Pillitteri JL, Gitchell JG (2008) Use of smoking-cessation treatments in the United States. Am J Prev Med 34:102–111
Stolerman IP, Jarvis MJ (1995) The scientific case that nicotine is addictive. Psychopharmacology (Berlin) 117:2–10, discussion 14–20
Vlachou S, Guery S, Froestl W, Banerjee D, Benedict J, Finn MG, Markou A (2011) Repeated administration of the GABAB receptor positive modulator BHF177 decreased nicotine self-administration, and acute administration decreased cue-induced reinstatement of nicotine seeking in rats. Psychopharmacology (Berlin) 215:117–128
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
This work was supported by the National Institutes of Health grant DA11946 to AM. AR-N was supported by the National Science Foundation Training Grant HRD-0331537 to California State University, and MSD was supported by Tobacco-Related Disease Research Program (TRDRP) of the State of California Individual Postdoctoral Fellowship 19FT-0045. The authors thank Mr. Michael Arends for editorial assistance.
Conflicts of interest
Athina Markou has received contract research support from Bristol-Myers Squibb Co., F. Hoffman-La Roche, Pfizer, and Astra-Zeneca, and honoraria/consulting fees from Abbott GmbH and Company, AstraZeneca, and Pfizer during the past 3 years. Dr. Markou has a patent on the use of metabotropic glutamate compounds for the treatment of nicotine dependence. The remaining authors report no financial conflicts of interests.
Ana M. Ramirez-Niño and Manoranjan S. D'Souza have contributed equally in the preparation of this manuscript.
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Ramirez-Niño, A.M., D’Souza, M.S. & Markou, A. N-acetylcysteine decreased nicotine self-administration and cue-induced reinstatement of nicotine seeking in rats: comparison with the effects of N-acetylcysteine on food responding and food seeking. Psychopharmacology 225, 473–482 (2013). https://doi.org/10.1007/s00213-012-2837-3