Nicotine and cigarette smoke modulate Nrf2-BDNF-dopaminergic signal and neurobehavioral disorders in adult rat cerebral cortex

Hum Exp Toxicol. 2018 May;37(5):540-556. doi: 10.1177/0960327117698543. Epub 2017 Jun 23.


Background: Nicotine and cigarette smoking (CS) are associated with addiction behavior, drug-seeking, and abuse. However, the mechanisms that mediate this association especially, the role of brain-derived neurotrophic factor (BDNF), dopamine (DA), and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling in the cerebral cortex, are not fully known. Therefore, we hypothesized that overexpression of BDNF and DA, and suppression of Nrf2 contribute to several pathological and behavioral alterations in adult cerebral cortex. Methodology/Principal Observations: We treated Wistar rats with different doses of oral nicotine and passive CS for 4-week (short-term) and 12-week (long-term) duration, where doses closely mimic the human smoking scenario. Our result showed dose-dependent association of anxiogenic and depressive behavior, and cognitive interference with neurodegeneration and DNA damage in the cerebral cortex upon exposure to nicotine/CS as compared to the control. Further, the results are linked to upregulation of oxidative stress, overexpression of BDNF, DA, and DA marker, tyrosine hydroxylase (TH), with concomitant downregulation of ascorbate and Nrf2 expression in the exposed cerebral cortex when compared with the control.

Conclusion/significance: Overall, our data strongly suggest that the intervention of DA and BDNF, and depletion of antioxidants are important factors during nicotine/CS-induced cerebral cortex pathological changes leading to neurobehavioral impairments, which could underpin the novel therapeutic approaches targeted at tobacco smoking/nicotine's neuropsychological disorders including cognition and drug addiction.

Keywords: BDNF; Nicotine; Nrf2; cerebral cortex behavior; cigarette smoking; dopamine; molecular mechanism; oxidative stress.

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Brain-Derived Neurotrophic Factor / metabolism*
  • Cerebral Cortex / drug effects*
  • Cerebral Cortex / metabolism
  • Dopamine / metabolism*
  • NF-E2-Related Factor 2 / metabolism*
  • Nicotine / toxicity*
  • Rats, Wistar
  • Signal Transduction
  • Smoke / adverse effects*
  • Tobacco Smoke Pollution / adverse effects*
  • Tobacco*


  • Brain-Derived Neurotrophic Factor
  • NF-E2-Related Factor 2
  • Smoke
  • Tobacco Smoke Pollution
  • Nicotine
  • Dopamine