Altered mRNA Levels of Stress-Related Peptides in Mouse Hippocampus and Caudate-Putamen in Withdrawal after Long-Term Intermittent Exposure to Tobacco Smoke or Electronic Cigarette Vapour

Int J Mol Sci. 2021 Jan 9;22(2):599. doi: 10.3390/ijms22020599.


Nicotine addiction is a severe public health problem. The aim of this study was to investigate the alterations in key neurotransmissions after 60 days of withdrawal from seven weeks of intermittent cigarette smoke, e-cigarette vapours, or an e-cigarette vehicle. In the nicotine withdrawal groups, increased depressive and anxiety/obsessive-compulsive-like behaviours were demonstrated in the tail suspension, sucrose preference and marble burying tests. Cognitive impairments were detected in the spatial object recognition test. A significant increase in Corticotropin-releasing factor (Crf) and Crf1 mRNA levels was observed, specifically after cigarette withdrawal in the caudate-putamen nucleus (CPu). The nociceptin precursor levels were reduced by cigarette (80%) and e-cigarette (50%) withdrawal in the CPu. The delta opioid receptor showed a significant reduction in the hippocampus driven by the exposure to an e-cigarette solubilisation vehicle, while the mRNA levels doubled in the CPu of mice that had been exposed to e-cigarettes. Withdrawal after exposure to e-cigarette vapour induced a 35% Bdnf mRNA decrease in the hippocampus, whereas Bdnf was augmented by 118% by cigarette withdrawal in the CPu. This study shows that long-term withdrawal-induced affective and cognitive symptoms associated to lasting molecular alterations in peptidergic signalling may determine the impaired neuroplasticity in the hippocampal and striatal circuitry.

Keywords: Bdnf; Crf; Crf receptors; addiction models; e-cigarette; nicotine addiction; nociceptin; opioid peptides; opioid receptors; orexin receptors.

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / genetics
  • Caudate Nucleus / drug effects
  • Caudate Nucleus / metabolism
  • Caudate Nucleus / physiopathology
  • Corticotropin-Releasing Hormone / genetics
  • Down-Regulation / drug effects
  • E-Cigarette Vapor / adverse effects*
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Hippocampus / physiopathology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Opioid Peptides / genetics
  • Orexins / genetics
  • Putamen / drug effects
  • Putamen / metabolism
  • Putamen / physiopathology
  • RNA, Messenger / genetics*
  • Receptors, Corticotropin-Releasing Hormone / genetics
  • Receptors, Opioid / genetics
  • Substance Withdrawal Syndrome / etiology
  • Substance Withdrawal Syndrome / genetics*
  • Substance Withdrawal Syndrome / physiopathology
  • Tobacco Smoke Pollution / adverse effects*
  • Up-Regulation / drug effects


  • Bdnf protein, mouse
  • Brain-Derived Neurotrophic Factor
  • E-Cigarette Vapor
  • Opioid Peptides
  • Orexins
  • RNA, Messenger
  • Receptors, Corticotropin-Releasing Hormone
  • Receptors, Opioid
  • Tobacco Smoke Pollution
  • CRF receptor type 1
  • Corticotropin-Releasing Hormone