• GOFARANA WILAR Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jl Raya Bandung-Sumedang KM 20,5 Desa Hegarmanah, Kecamatan Jatinangor, Sumedang, 45363 Indonesia, Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai-shi, 980-8579 Japan
  • KOHJI FUKUNAGA Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai-shi, 980-8579 Japan



Nicotine dependence, CaMKII, ERK, Conditioned place preference, Preference score


Objective: Nicotine is an active compound in tobacco and has a rewarding effect in the central nervous system (CNS), which may lead to dependence. Although nicotine dependence is elucidated by brain mechanisms, synaptic molecular substrates underlying the dependence remain unclear. We hypothesized that reward signaling is mediated by dopamine and glutamate receptors, in where calcium/calmodulin-dependent kinase II (CaMKII) and extracellular signal-regulated kinase (ERK) may mediate the synaptic signaling of dependence.

Methods: To investigate the roles of both CaMKII and ERK on nicotine dependence were assessed by conditioned place preference (CPP) methods followed by dissection. One day after conditioning, preference scores were measured to evaluate nicotine dependence. Mice were sacrificed and their striatum were dissected out for immunoblotting analyses of CaMKII and ERK phosphorylation.

Results: Nicotine-induced conditioned place preference as a symptom of nicotine dependence. CaMKII and ERK phosphorylation in striatum significantly increased along with the development of nicotine dependence.

Conclusion: We should next apply pharmacological strategies to manipulate CaMKII and ERK signaling. In particular, disruption of reconsolidation by disrupting CaMKII and ERK signaling may propose an attractive therapeutic approach to inhibit nicotine dependence.


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Benowitz NL. Nicotine addiction. Prim Care. 1999;26(3):611-31. doi: 10.1016/s0095-4543(05)70120-2, PMID 10436290.

Henningfield JE, Miyasato K, Jasinski DR. Abuse liability and pharmacodynamic characteristics of intravenous and inhaled nicotine. J Pharmacol Exp Ther. 1985;234(1):1-12. PMID 4009494.

Changeux JP. Nicotine addiction and nicotinic receptors: lessons from genetically modified mice. Nat Rev Neurosci. 2010;11(6):389-401. doi: 10.1038/nrn2849, PMID 20485364.

Leslie FM, Mojica CY, Reynaga DD. Nicotinic receptors in addiction pathways. Mol Pharmacol. 2013;83(4):753-8. doi: 10.1124/mol.112.083659, PMID 23247824.

Albuquerque EX, Pereira EFR, Alkondon M, Rogers SW. Mammalian nicotinic acetylcholine receptors: from structure to function. Physiol Rev. 2009;89(1):73-120. doi: 10.1152/physrev.00015.2008, PMID 19126755.

Shen JX, Yakel JL. Nicotinic acetylcholine receptor-mediated calcium signaling in the nervous system. Acta Pharmacol Sin. 2009;30(6):673-80. doi: 10.1038/aps.2009.64, PMID 19448647.

Xiao RP, Cheng H, Lederer WJ, Suzuki T, Lakatta EG. Dual regulation of Ca2+/calmodulin-dependent kinase II activity by membrane voltage and by calcium influx. Proc Natl Acad Sci USA. 1994;91(20):9659-63. doi: 10.1073/pnas.91.20.9659, PMID 7937825.

Tahara S, Fukuda K, Kodama H, Kato T, Miyoshi S, Ogawa S. Potassium channel blocker activates extracellular signal-regulated kinases through Pyk2 and epidermal growth factor receptor in rat cardiomyocytes. J Am Coll Cardiol. 2001;38(5):1554-63. doi: 10.1016/s0735-1097(01)01558-3, PMID 11691539.

Sheng M, Kim MJ. Postsynaptic signaling and plasticity mechanisms. Science. 2002;298(5594):776-80. doi: 10.1126/science.1075333, PMID 12399578.

Valjent E, Corvol JC, Pages C, Besson MJ, Maldonado R, Caboche J. Involvement of the extracellular signal-regulated kinase cascade for cocaine-rewarding properties. J Neurosci. 2000;20(23):8701-9. doi: 10.1523/JNEUROSCI.20-23-08701.2000, PMID 11102476.

Chwang WB, O’Riordan KJ, Levenson JM, Sweatt JD. ERK/MAPK regulates hippocampal histone phosphorylation following contextual fear conditioning. Learn Mem. 2006;13(3):322-8. doi: 10.1101/lm.152906, PMID 16741283.

Benowitz NL, Porchet H, Sheiner L, Jacob P. Nicotine absorption and cardiovascular effects with smokeless tobacco use: comparison with cigarettes and nicotine gum. Clin Pharmacol Ther. 1988;44(1):23-8. doi: 10.1038/clpt.1988.107, PMID 3391001.

Wilar G, Shinoda Y, Sasaoka T, Fukunaga K. Crucial role of dopamine D2 receptor signaling in nicotine-induced conditioned place preference. Mol Neurobiol. 2019;56(12):7911-28. doi: 10.1007/s12035-019-1635-x, PMID 31129809.

Fukunaga K, Goto S, Miyamoto E. Immunohistochemical localization of Ca2+/calmodulin-dependent protein kinase II in rat brain and various tissues. J Neurochem. 1988;51(4):1070-8. doi: 10.1111/j.1471-4159.1988.tb03070.x, PMID 3047316.

Roux PP, Blenis J. ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol Mol Biol Rev. 2004;68(2):320-44. doi: 10.1128/MMBR.68.2.320-344.2004, PMID 15187187.

Risinger FO, Oakes RA. Nicotine-induced conditioned place preference and conditioned place aversion in mice. Pharmacol Biochem Behav. 1995;51(2-3):457-61. doi: 10.1016/0091-3057(95)00007-j, PMID 7667368.

Carboni E, Vacca C. Conditioned place preference. Drugs Abus Neurol Rev Protoc. 2002;79:481-98.

Le Foll B, Goldberg SR. Nicotine induces conditioned place preferences over a large range of doses in rats. Psychopharmacol (Berl). 2005;178(4):481-92. doi: 10.1007/s00213-004-2021-5, PMID 15765262.

Brielmaier JM, McDonald CG, Smith RF. Nicotine place preference in a biased conditioned place preference design. Pharmacol Biochem Behav. 2008;89(1):94-100. doi: 10.1016/j.pbb.2007.11.005, PMID 18086490.

Calcagnetti DJ, Schechter MD. Nicotine place preference using the biased method of conditioning. Prog Neuropsychopharmacol Biol Psychiatry. 1994;18(5):925-33. doi: 10.1016/0278-5846(94)90108-2, PMID 7972862.

Bardo MT, Bevins RA. Conditioned place preference: what does it add to our preclinical understanding of drug reward? Psychopharmacol (Berl). 2000;153(1):31-43. doi: 10.1007/s002130000569, PMID 11255927.

Cunningham CL, Dickinson SD, Grahame NJ, Okorn DM, McMullin CS. Genetic differences in cocaine-induced conditioned place preference in mice depend on conditioning trial duration. Psychopharmacol (Berl). 1999;146(1):73-80. doi: 10.1007/s002130051090, PMID 10485967.

Govind AP, Vezina P, Green WN. Nicotine-induced upregulation of nicotinic receptors: underlying mechanisms and relevance to nicotine addiction. Biochem Pharmacol. 2009;78(7):756-65. doi: 10.1016/j.bcp.2009.06.011, PMID 19540212.

Rogers SW, Gahring LC. Upregulation of nicotinic acetylcholine receptor alph4+beta2 through a ligand-independent PI3Kbeta mechanism that is enhanced by TNFalpha and the Jak2/p38MAPK pathways. PLOS ONE. 2015;10(11):e0143319. doi: 10.1371/journal.pone.0143319, PMID 26619345.

Nguyen HN, Rasmussen BA, Perry DC. Subtype-selective up-regulation by chronic nicotine of high-affinity nicotinic receptors in rat brain demonstrated by receptor autoradiography. J Pharmacol Exp Ther. 2003;307(3):1090-7. doi: 10.1124/jpet.103.056408. PMID 14560040.

Nomikos GG, Schilström B, Hildebrand BE, Panagis G, Grenhoff J, Svensson TH. Role of alpha7 nicotinic receptors in nicotine dependence and implications for psychiatric illness. Behav Brain Res. 2000;113(1-2):97-103. doi: 10.1016/s0166-4328(00)00204-7, PMID 10942036.

Hurst R, Rollema H, Bertrand D. Nicotinic acetylcholine receptors: from basic science to therapeutics. Pharmacol Ther. 2013;137(1):22-54. doi: 10.1016/j.pharmthera.2012.08.012, PMID 22925690.

Gubbins EJ, Gopalakrishnan M, Li J. Alpha7 nAChR-mediated activation of MAP kinase pathways in PC12 cells. Brain Res. 2010;1328:1-11. doi: 10.1016/j.brainres.2010.02.083, PMID 20211606.

Jackson KJ, Muldoon PP, Walters C, Damaj MI. Neuronal calcium/calmodulin-dependent protein kinase II mediates nicotine reward in the conditioned place preference test in mice. Behav Pharmacol. 2016;27(1):50-6. doi: 10.1097/FBP.0000000000000189, PMID 26292186.

Picconi B, Gardoni F, Centonze D, Mauceri D, Cenci MA, Bernardi G, Calabresi P, Di Luca M. Abnormal Ca2+calmodulin-dependent protein kinase II function mediates synaptic and motor deficits in experimental parkinsonism. J Neurosci. 2004;24(23):5283-91. doi: 10.1523/JNEUROSCI.1224-04.2004, PMID 15190099.

Silva AJ, Paylor R, Wehner JM, Tonegawa S. Impaired spatial learning in alpha-calcium-calmodulin kinase II mutant mice. Science. 1992;257(5067):206-11. doi: 10.1126/science.1321493, PMID 1321493.

Nakayama H, Numakawa T, Ikeuchi T, Hatanaka H. Nicotine-induced phosphorylation of extracellular signal-regulated protein kinase and CREB in PC12h cells. J Neurochem. 2001;79(3):489-98. doi: 10.1046/j.1471-4159.2001.00602.x, PMID 11701752.

Chen RJ, Ho YS, Guo HR, Wang YJ. Rapid activation of Stat3 and ERK1/2 by nicotine modulates cell proliferation in human bladder cancer cells. Toxicol Sci. 2008;104(2):283-93. doi: 10.1093/toxsci/kfn086, PMID 18448488.



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