Nicotine-induced memory impairment by increasing brain oxidative stress

Lucian Hritcu 1 , Alin Ciobica,  and Lucian Gorgan 1
  • 1 Department of Biology, “Alexandru Ioan Cuza” University, 700506, Iasi, Romania
  • 2 Laboratory for Experimental and Applied Physiology, Romanian Academy, 700505, Iasi, Romania


Male Wistar rats were subjected to chronic nicotine treatment (0.3 mg/kg; 7 continuous days) and their memory performance was studied by means of Y-maze and multi-trial passive avoidance tasks. Nicotine significantly decreased spontaneous alternation in Y-maze task and step-through-latency in the multi-trial passive avoidance task, suggesting effects on both short-term memory and long-term memory, respectively. In addition, nicotine induced neuronal apoptosis, DNA fragmentation, reduced antioxidant enzymes activity, and increased production of lipid peroxidation and reactive oxygen species, suggesting pro-oxidant activity. Our results provide further support that nicotine-induced memory impairment is due to an increase in brain oxidative stress in rats.

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • [1] Zeidler R., Albermann K., Lang S., Nicotine and apoptosis, Apoptosis, 2007, 12, 1927–1943

  • [2] Swan G.E., Lessov-Schlaggar C.N., The effects of tobacco smoke and nicotine on cognition and the brain, Neuropsychol. Rev., 2007, 17, 259–273

  • [3] Mihailescu S., Drucker-Colin R., Nicotine, brain nicotinic receptors, and neuropsychiatric disorders, Arch. Med. Res., 2000, 31, 131–144

  • [4] Picciotto M.R., Zoli M., Neuroprotection via nAChRs: the role of nAChRs in neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease, Front Biosci., 2008, 13, 492–504

  • [5] Araki H., Suemaru K., Gomita Y., Neuronal nicotinic receptor and psychiatric disorders: functional and behavioral effects of nicotine, Jpn. J. Pharmacol., 2002, 88, 133–138

  • [6] McEvoy J.P., Freudenreich O., McGee M., VanderZwaag C., Levin E., Rose J., Clozapine decreases smoking in patients with chronic schizophrenia, Biol. Psychiatry, 1995, 37, 550–552

  • [7] McEvoy J.P., Freudenreich O., Wilson W.H., Smoking and therapeutic response to clozapine in patients with schizophrenia, Biol. Psychiatry, 1999, 46, 125–129

  • [8] Stage K.B., Glassman A.H., Covey L.S., Depression after smoking cessation: case reports, J. Clin. Psychiatry, 1996, 57, 467–469

  • [9] Levin E.D., Rezvani A.H., Nicotinic interactions with antipsychotic drugs, models of schizophrenia and impacts on cognitive function, Biochem. Pharmacol., 2007, 74, 1182–1191

  • [10] McGehee D.S., Nicotine and synaptic plasticity in prefrontal cortex, Sci STKE, 2007, 399, 44

  • [11] Biala G., Kruk M., Cannabinoid receptor ligands suppress memory-related effects of nicotine in the elevated plus maze test in mice, Behav. Brain Res., 2008, 192, 198–202

  • [12] Ahmadi S., Zarrindast M.R., Haeri-Rohani A., Rezayof A., Nouri M., Nicotine improves morphine-induced impairment of memory: possible involvement of N-methyl-D-aspartate receptors in the nucleus accumbens, Dev. Neurobiol., 2007, 67, 1118–1127

  • [13] Cincotta S., Yorek M.S., Moschak T.M., Lewis S.R., Rodefer J.S., Selective nicotinic acetylcholine receptor agonists: potential therapies for neuropsychiatric disorders with cognitive dysfunction, Curr. Opin. Investig. Drugs, 2008, 9, 47–56

  • [14] Sola E., Capsoni S., Rosato-Siri M., Cattaneo A., Cherubini E., Failure of nicotine-dependent enhancement of synaptic efficacy at Schaffer-collateral CA1 synapses of AD11 anti-nerve growth factor transgenic mic, Eur. J. Neurosci., 2006, 24, 1252–1264

  • [15] Matta S.G., Elberger A.J., Combined exposure to nicotine and ethanol throughout full gestation results in enhanced acquisition of nicotine self-administration in young adult rat offspring, Psychopharmacology (Berl.), 2007, 193, 199–213

  • [16] Dunnet S.B., Martel F.L., Proactive interference effects on short-term memory in rats, Basic parameters and drug effects, Behav. Neurosci., 1990, 104, 655–665

  • [17] Heisham S.J., Taylor R.C., Henningfield J.E., Nicotine and smoking: a review of effects on human performance, Exp. Clin. Psychopharmacol., 1994, 2, 345–395

  • [18] Eppolito A.K., Smith R.F., Long-term behavioral and developmental consequences of pre- and perinatal nicotine, Pharmacol. Biochem. Behav., 2006, 85, 835–841

  • [19] Gallinat J., Lang U.E., Jacobsen L.K., Bajbouj M., Kalus P., von Haebler D., et al., Abnormal hippocampal neurochemistry in smokers: evidence from proton magnetic resonance spectroscopy at 3 T, J. Clin. Psychopharmacol., 2007, 27, 80–84

  • [20] Oddo S., Caccamo A., Green K.N., Liang K., Tran L., Chen Y., et al., Chronic nicotine administration exacerbates tau pathology in a transgenic model of Alzheimer’s disease, Proc. Natl. Acad. Sci. USA, 2005, 102, 3046–3051

  • [21] Chong Z.Z., Li F., Maiese K., Stress in the brain: Novel cellular mechanisms of injury linked to Alzheimer’s disease, Brain Res. Rev., 2005, 49, 1–21

  • [22] Mazza M., Pomponi M., Janiri L., Bria P., Mazza S., Omega-3 fatty acids and antioxidants in neurological and psychiatric diseases: An overview, Prog. Neuropsychopharmacol. Biol. Psychiatry, 2007, 31, 12–26

  • [23] Mariani E., Polidori M.C., Cherubini A., Mecocci P., Oxidative stress in brain aging, and degenerative and vascular diseases: An overview, J. Chromatogr. B, 2005, 27, 65–75

  • [24] Butterfield D.A., Perluigi M., Sultana R., Oxidative stress in Alzheimer’s disease brain: New insights from redox proteomics, Eur. J. Pharmacol., 2006, 545, 39–50

  • [25] Suleyman H., Gumustekin K., Taysi S., Keles S., Oztasan N., Aktas O., Beneficial effects of Hippophae rhamnoides L. on nicotine induced oxidative stress in rat blood compared with vitamin E, Biol. Pharm. Bull., 2002, 25, 1133–1136

  • [26] Sudheer A.R., Kalpana C., Srinivasan M., Menon V.P., Ferulic acid modulates altered lipid profiles and prooxidant/antioxidant status in circulation during nicotine-induced toxicity: a dosedependent study, Toxicol. Mech. Method, 2005, 15, 375–381

  • [27] Sudheer A.R., Muthukumaran S., Devipriya N., Menon V.P., Ellagic acid, a natural polyphenol protects rat peripheral blood lymphocytes against nicotine-induced cellular and DNA damage in vitro: with the comparison of N-acetylcysteine, Toxicology, 2007, 230, 11–21

  • [28] Srinivasan K.N., Pugalendi K.V., Effect of excessive intake of thermally oxidized sesame oil on lipids, lipid peroxidation and antioxidants status in rats, Indian J. Exp. Biol., 2000, 38, 777–780

  • [29] Ashakumary L., Vijayammal P.L., Additive effect of alcohol and nicotine on lipid peroxidation and antioxidant defence mechanism in rats, J. Appl. Toxicol., 1996, 16, 305–308<305::AID-JAT353>3.0.CO;2-F

  • [30] Zhang J., Jiang S., Watson R.R., Antioxidant supplementation prevents oxidation and inflammatory responses induced by sidestream cigarette smoke in old mice, Environ. Health Perspect., 2001, 109, 1007–1009

  • [31] Muthukumaran S., Sudheer A.R., Menon V.P., Nalini N., Protective effect of quercetin on nicotine-induced prooxidant and antioxidant imbalance and DNA damage in Wistar rats, Toxicology, 2008, 243, 207–215

  • [32] Chattopadhyay K., Chattopadhyay B.D., Effect of nicotine on lipid profile, peroxidation & antioxidant enzymes in female rats with restricted dietary protein, Indian J. Med. Res., 2008, 127, 571–576

  • [33] Zhang X.Y., Tan Y.L., Zhou D.F., Haile C.N., Wu G.Y., Cao L.Y., et al., Nicotine dependence, symptoms and oxidative stress in male patients with schizophrenia, Neuropsychopharmacology, 2007, 32, 2020–2024

  • [34] Halliwell H., Guttridge J.M.C., Free radicals and antioxidant protection: mechanisms and significance in toxicology and disease, Hum. Toxicol., 1988, 7, 7–13

  • [35] Karelson E., Bogdanovic N., Garlind A., Winblad B., Zilmer K., Kullisaar T., et al., The cerebrocortical areas in normal brain aging and in Alzheimer’s disease: noticeable differences in the lipid peroxidation level and in antioxidant defense, Neurochem. Res., 2001, 26, 353–361

  • [36] Yamada K., Noda Y., Hasegawa T., Komori Y., Nikai T., Sugihara H., et al., The role of nitric oxide in dizocilpine-induced impairment of spontaneous alternation behavior in mice, J. Pharmacol. Exp. Ther., 1996, 276, 460–466

  • [37] Hritcu L., Clicinschi M., Nabeshima T., Brain serotonin depletion impairs short-term memory, but not long-term memory in rats, Physiol. Behav., 2007, 91, 652–657

  • [38] Spilich G.J., June L., Renner J., Cigarette smoking and cognitive performance, Br. J. Addiction, 1992, 87, 1313–1326

  • [39] Guan Z.Z., Yu W.F., Nordberg A., Dual effects of nicotine on oxidative stress and neuroprotection in PC12 cells, Neurochem. Int., 2003, 43, 243–249

  • [40] Sachs C., Jonsson G., Mechanisms of action of 6-hydroxydopamine, Biochem. Pharmacol., 1975, 24, 1–8

  • [41] Perumal A.S., Gopal V.B., Tordzro W.K., Cooper T.B., Cadet J.L., Vitamin E attenuates the toxic effects of 6-hydroxydopamine on free radical scavenging systems in rat brain, Brain Res. Bull., 1992, 29, 699–701

  • [42] Kumar R., Agarwal A.K., Seth P.K., Free radical-generated neurotoxicity of 6-hydroxydopamine, J. Neurochem., 1995, 64, 1703–1707

  • [43] Pre J., Floch A.L., Vassay R., Lenoble C., Increased plasma level of fluorescent lipid peroxidation products in cigarette smokers, Med. Sci. Res., 1989, 17, 1029–1030

  • [44] Butterfield D.A., Lauderback C.M., Lipid peroxidation and protein oxidation in Alzheimer’s disease brain: potential causes and consequences involving amyloid beta-peptide-associated free radical oxidative stress, Free Radic. Biol. Med., 2002, 32, 1050–1060

  • [45] Coyle J.T., Puttfarcken P., Oxidative stress, glutamate, and neurodegenerative disorders, Science, 1993, 262, 689–695

  • [46] Kim H.C., Jhoo W.K., Choi D.Y., Im D.H., Shin E.J., Suh J.H., et al., Protection of methamphetamine nigrostriatal toxicity by dietary selenium, Brain Res., 1999, 851, 76–86

  • [47] Guo J., Chu M., Abbeyquaye T., Chen C.Y., Persistent nicotine treatment potentiates amplification of the dihydrofolate reductase gene in rat lung epithelial cells as a consequence of Ras activation, J. Biol. Chem., 2005, 280, 30422–30431

  • [48] Liu Q., Zhao B., Nicotine attenuates beta-amyloid peptide-induced neurotoxicity, free radical and calcium accumulation in hippocampal neuronal cultures, Br. J. Pharmacol., 2004, 141, 746–754

  • [49] Jang M.H., Shin M.C., Jung S.B., Lee T.H., Bahn G.H., Kwon Y.K., et al., Alcohol and nicotine reduce cell proliferation and enhance apoptosis in dentate gyrus, Neuroreport, 2002, 13, 1509–1513


Journal + Issues

Open Life Sciences (previously Central European Journal of Biology) is a fast growing OA journal, devoted to scholarly research in all areas of life sciences. The journal assures top quality of published data through critical peer review, editorial involvement throughout the whole publication process. Thanks to OA it also offers unrestricted access to published articles for all users.