Abstract
In this study, the inhibitory effect of L-theanine, an amino acid derivative of tea, on the rewarding effects of nicotine and its underlying mechanisms of action were studied. We found that L-theanine inhibited the rewarding effects of nicotine in a conditioned place preference (CPP) model of the mouse and reduced the excitatory status induced by nicotine in SH-SY5Y cells to the same extent as the nicotine receptor inhibitor dihydro-beta-erythroidine (DHβE). Further studies using high performance liquid chromatography, western blotting and immunofluorescence staining analyses showed that L-theanine significantly inhibited nicotine-induced tyrosine hydroxylase (TH) expression and dopamine production in the midbrain of mice. L-theanine treatment also reduced the upregulation of the α4, β2 and α7 nicotine acetylcholine receptor (nAChR) subunits induced by nicotine in mouse brain regions that related to the dopamine reward pathway, thus decreasing the number of cells that could react to nicotine. In addition, L-theanine treatment inhibited nicotine-induced c-Fos expression in the reward circuit related areas of the mouse brain. Knockdown of c-Fos by siRNA inhibited the excitatory status of cells but not the upregulation of TH induced by nicotine in SH-SY5Y cells. Overall, the present study showed that L-theanine reduced the nicotine-induced reward effects via inhibition of the nAChR-dopamine reward pathway. These results may offer new therapeutic strategies for treatment of tobacco addiction.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Gu D F, Kelly T N, Wu X, et al. Mortality attributable to smoking in China. N Engl J Med, 2009, 360: 150–159
McLellan A T, Lewis D C, O’Brien C P, et al. Drug dependence, a chronic medical illness: implications for treatment, insurance, and outcomes evaluation. JAMA, 2000, 284: 1689–1695
Mizoue T, Tokui N, Nishisaka K. Prospective study on the relation of cigarette smoking with cancer of the liver and stomach in an endemic region. Intern J Epidem, 2000, 29: 232–237
Oncken C, Gonzales D, Nides M, et al. Efficacy and safety of the novel selective nicotinic acetylcholine receptor partial agonist, varenicline, for smoking cessation. Arch Intern Med, 2006, 166: 1571–1577
Ray R, Schnoll R A, Lerman C. Nicotine dependence: biology, behavior, and treatment. Annu Rev Med, 2009, 60: 247–260
Rigotti A N. Treatment on tobacco use and dependence. N Engl J Med, 2002, 346: 506–512
Moxham J. Nicotine addiction. BMJ, 2000, 7232: 391–392
Picciotto M R, Zoli M, Rimondini R. Acetyl-choline receptors containing the β2 subunit are involved in the reinforcing properties of nicotine. Nature, 1998, 6663: 173–177
Tapper A R, McKinney S L, Nashmi R. Nicotine activation of α4* receptors: sufficient for reward, tolerance, and sensitization. Science, 2004, 306: 1029–1032
Bencherif M, Fowler K, Lukas R J. Mechanisms of up-regulation of neuronal nicotinic acetylcholine receptors in clonal cell lines and primary cultures of fetal rat brain. J Pharmacol Exp Ther, 1995, 275: 987–999
Peng X, Gerzanich V, Anand R. Nicotine-induced increase in neuronal nicotinic receptors results from a decrease in the rate of receptor turnover. Mol Pharmacol, 1994, 46: 523–530
Breese C R, Marks M J, Logel J. Effect of smoking history on 3H nicotine binding in human postmortem brain. J Pharmacol Exp Ther, 1997, 282: 7–13
Besson M, Granon S, Mameli-Engvall M. Long-term effects of chronic nicotine exposure on brain nicotinic receptors. Proc Natl Acad Sci USA, 2007, 104: 8155–8160
Nestler E J. Molecuhr mechanisms of drug addiction. Neu ropharm, 2004, 47: 24–32
Eschenauer G, Sweet B V. Pharmacology and therapeutic uses of theanine. Am J Health-Syst Ph, 2006, 63: 26–30
Yan J Q, Di X J, Liu C Y, et al. Cessation effect of tea filter on cigarette smoking addiction. Sci China Life Sci, 2010, 53: 533–541
Nguyen H N, Rasmussen B A, Perry D C. Subtypeselective up-regulation by chronic nicotine of high-affinity nicotinic receptors in rat brain demonstrated by receptor autoradiography. J Pharmacol Exp Ther, 2003, 307: 1090–1097
Huang E Y, Liu T C, Tao P L. Co-administration of dextromethorphan with morphine attenuates morphine rewarding effect and related dopamine releases at the nucleus accumbens. NaunynSchmiedebergs Arch Pharmacol, 2003, 368: 386–392
Laviolette S R, Nader K, Kooy D V. Motivational state determines the functional role of the mesolimbic dopamine system in the mediation of opiate reward processes. Behav Brain Res, 2002, 129: 17–29
Jiang H, Luan Z, Wang J, et al. Neuroprotective effects of iron chelator desferal on dopaminergic neurons in the substantia nigra of rats with iron-overload. Neurochem Int, 2006, 49: 605–609
Shachar B D, Youdim M B. Selectivity of melaninized nigra-striatal dopamine neurons to degeneration in Parkinson’s disease may depend on iron±melanin interaction. J Neural Transm Suppl, 1990, 29: 251–255
Bezard E, Dovero S, Bioulac B, et al. Kinetics of nigral degeneration in a chronic model of MPTP-treated mice. Neurosci Lett, 199, 234: 43–45
Gross C E, Ravenscroft P, Dovero S, et al. Pattern of levodopa-induced striatal changes is different in normal and MPTP-lesioned mice. J Neurochem, 2003, 84: 1246–1251
Miller R G. Simultaneous Statistical Inference. New York: Springer, 1981. 230
Mansvelder H D, Keath J R, McGehee D S. Synaptic mechanisms underlie nicotine-induced excitability of brain reward areas. Neuron, 2002, 33: 905–919
Panagis G, Nisell M, Nomikos G G. Nicotine injections into the Ventral tegmental area increase locomotion and Fos-like immunoreactivity in the nucleus ac-cumbens of the rat. Brain Res, 1996, 730: 133–142
Rahman S, Zhang J, Corrigall W A. Effects of acute and chronic nicotine on somatodendritic dopamine release of the rat ventral tegmental area: in vivo microdialysis. Neurosci Lett, 2003, 348: 61–64
Ferrafi R, Le Novere N, Picciotto M R. Acute and long-term changes in the mesolimbic dopamine pathway after systemic or local single nicotine injections. Eur J Neurosci, 2002, 15: 1810–1818
Corrigall W A, Coen K M, Adamson K L. Self-administered nicotine activates the mesolimbic dopamine system through the ventral tegmental area. Brain Res, 1994, 653: 278–284
Markou A, Paterson N E. The nicotinic antagonist methyllycaconitine has differential effects on nicotine self-administration and nicotine withdrawal in the rat. Nicotine Tob Res, 2001, 3: 361–373
Lapchak P A, Araujo D M, Quirion R. Effect of chronic nicotine treatment on nicotinic autoreceptor function and N-[3H] methylcar-bamylcholine binding sites in the rat brain. J Neurochem, 1989, 52: 483–491
Lapin E P, Maker H S, Sershen H. Action of nicotine on accumbens dopamine and attenuation with repeated administration. Eur J Pharmacol, 1989, 160: 53–59
Marks M J, Burch J B, Collins A C. Effects of chronic nicotine infusion on tolerance development and nicotinic receptors. J Pharmacol Exp Ther, 1983, 226: 817–825
Sharp B M, Beyer H S, Levine A S. Attenuation of the plasma prolactin response to restraint stress after acute and chronic administration of nicotine to rats. J Pharmacol Exp Ther, 1987, 241: 438–442
Shram M J, Funk D, Li Z. Acute nicotine enhances c-FOS mRNA expression differentially in reward-related substrates of adolescent and adult rat brain. Neuro Sci, 2007, 418: 286–291
Salminen O, Seppa T, Gaddnas H. The effects of acute nicotine on the metabolism Of dopamine and the expression of Fos protein in striatal and limbic brain areas of rats during Chronic nicotine infusion and its withdrawal. J Neuro Sci, 1999, 19: 8145–8151
Marks M J, Grady S R, Yang J M. Desensitization of nicotine-stimulated 86Rb+ efflux from mouse brain synaptosomes. J Neurochem, 1994, 63: 2125–2135
Schwartz R D. Nicotinic cholinergic receptor binding sites in the brain: regulation in vivo. Science, 1983, 220: 214–216
Benwell M E M, Balfour D J K. The effects of acute and repeated nicotine treatment on nucleus accumbens dopamine and locomotor activity. Br J Pharmacol, 1992, 105: 849–856
Balbani A P S, Montovani J C. Methods for smoking cessation and treatment of nicotine dependence. Rev Bras Otorrinolaringol, 2005, 71: 820–826
Ray R, Schnoll R A, Lerman C. Nicotine dependence: biology, behavior, and treatment. Annu Rev Med, 2009, 60: 247–260
Rigotti A N. Treatment on tobacco use and dependence. N Engl J Med, 2002, 346: 506–512
Peng R L, Wang S L. Nicotine sublingual tablet for smoking cessation in 115 cases: a double-blind randomized placebo-controlled clinical trial. J Clin Rehabilit Tissue Engin Res, 2007, 11: 10443–10446
Liu Q, Tao Y, Zhao B L. ESR study on scavenging effect of nicotine on free radicals. Appl Mag Reson, 2003, 24: 105–112
Liu Q, Zhao B L. Nicotine attenuates β-amyloid peptide induced neurotoxicity, free radical and calcium accumulation in hippocampal neuronal cultures. Brit J Pharmoco, 2004, 1141: 746–754
Xie Y X, Bezard E, Zhao B L. Unraveling the receptor-independent neuroprotective mechanism in mitochondria. J Biol Chem, 2005, 396: 84–92
Zhang J, Liu Q, Liu N Q, et al. Nicotine reduces β-amyloidosis by regulating metal homeostasis. FASEB J, 2006, 20: 1212–1214
Liu Q, Zhang J, Qin C, et al. Dissecting the signalling pathway of nicotine-mediated neuroprotection in a mouse Alzheimer disease model. FASEB J, 2007, 21: 61–73
Zhao B L. The molecular mechanism of treatment of Alzheimer’s disease and Parkinson’s disease by nicotine. Acta Biophys China, 2007, 23: 81–92
Di X, Yan J, Zha Y, et al. L-theanine protects the APP (Swedish mutation) transgenic SH-SY5Y cell against glutamate-induced excitotoxicity via inhibition of the NMDA receptor pathway. Neuroscience, 2010, 168: 778–786
Author information
Authors and Affiliations
Corresponding author
Additional information
Contributed equally to this work
This article is published with open access at Springerlink.com
Rights and permissions
Open Access This article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
About this article
Cite this article
Di, X., Yan, J., Zhao, Y. et al. L-theanine inhibits nicotine-induced dependence via regulation of the nicotine acetylcholine receptor-dopamine reward pathway. Sci. China Life Sci. 55, 1064–1074 (2012). https://doi.org/10.1007/s11427-012-4401-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11427-012-4401-0