Persistent cognitive and affective alterations at late withdrawal stages after long-term intermittent exposure to tobacco smoke or electronic cigarette vapour: Behavioural changes and their neurochemical correlates

Pharmacol Res. 2020 Aug:158:104941. doi: 10.1016/j.phrs.2020.104941. Epub 2020 May 23.


Smoking cessation induces a withdrawal syndrome associated with anxiety, depression, and impaired neurocognitive functions, but much less is known about the withdrawal of e-cigarettes (e-CIG). We investigated in Balb/c mice the behavioural and neurochemical effects of withdrawal for up to 90 days after seven weeks' intermittent exposure to e-CIG vapour or cigarette smoke (CIG). The withdrawal of e-CIG and CIG induced early behavioural alterations such as spatial memory deficits (spatial object recognition task), increased anxiety (elevated plus maze test) and compulsive-like behaviour (marble burying test) that persisted for 60-90 days. Notably, attention-related (virtual object recognition task) and depression-like behaviours (tail suspension and sucrose preference tests) appeared only 15-30 days after withdrawal and persisted for as long as up to 90 days. At hippocampal level, the withdrawal-induced changes in the levels of AMPA receptor GluA1 and GluA2/3 subunits, PSD 95 protein, corticotropin-releasing factor (Crf) and Crf receptor 1 (CrfR1) mRNA were biphasic: AMPA receptor subunit and PSD95 protein levels initially remained unchanged and decreased after 60-90 days, whereas Crf/CrfR1 mRNA levels initially increased and then markedly decreased after 60 days. These late reductions correlated with the behavioural impairments, particularly the appearance of depression-like behaviours. Our findings show that major behavioural and neurochemical alterations persist or even first appear late after the withdrawal of chronic CIG smoke or e-CIG vapour exposure, and underline importance of conducting similar studies of humans, including e-CIG vapers.

Keywords: AMPA glutamate receptors; Behaviour; Cigarette smoke; Crf; Crf receptors; NMDA; Withdrawal; e-cigarette vapour.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Affect / drug effects*
  • Affect / physiology
  • Animals
  • Cigarette Smoking / adverse effects*
  • Cigarette Smoking / metabolism
  • Cognition / drug effects*
  • Cognition / physiology
  • E-Cigarette Vapor / administration & dosage
  • E-Cigarette Vapor / adverse effects*
  • Hippocampus / chemistry
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Inhalation Exposure / adverse effects
  • Male
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Mice
  • Mice, Inbred BALB C
  • Recognition, Psychology / drug effects
  • Recognition, Psychology / physiology
  • Substance Withdrawal Syndrome / metabolism*
  • Substance Withdrawal Syndrome / psychology
  • Tobacco Smoke Pollution / adverse effects*


  • E-Cigarette Vapor
  • Tobacco Smoke Pollution