Developmental effects of acute, chronic, and withdrawal from chronic nicotine on fear conditioning

Neurobiol Learn Mem. 2012 May;97(4):482-94. doi: 10.1016/j.nlm.2012.04.003. Epub 2012 Apr 11.


Pre-adolescence and adolescence are developmental periods associated with increased vulnerability for tobacco addiction, and exposure to tobacco during these periods may lead to long-lasting changes in behavioral and neuronal plasticity. The present study examined the short- and long-term effects of nicotine and nicotine withdrawal on fear conditioning in pre-adolescent, adolescent, and adult mice, and potential underlying substrates that may mediate the developmental effects of nicotine, such as changes in nicotinic acetylcholine receptor (nAChR) binding, CREB expression, and nicotine metabolism. Age-related differences existed in sensitivity to the effects of acute nicotine, chronic nicotine and nicotine withdrawal on contextual fear conditioning (no changes in cued fear conditioning were seen); younger mice were more sensitive to the acute effects and less sensitive to the effects of nicotine withdrawal 24 h post treatment cessation. Developmental differences in nAChR binding were associated with the effects of nicotine withdrawal on contextual learning. Developmental differences in nicotine metabolism and CREB expression were also observed, but were not related to the effects of nicotine withdrawal on contextual learning 24 h post treatment. Chronic nicotine exposure during pre-adolescence or adolescence, however, produced long-lasting impairments in contextual learning that were observed during adulthood, whereas adult chronic nicotine exposure did not. These developmental effects could be related to changes in CREB. Overall, there is a developmental shift in the effects of nicotine on hippocampus-dependent learning and developmental exposure to nicotine results in adult cognitive deficits; these changes in cognition may play an important role in the development and maintenance of nicotine addiction.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Age Factors
  • Animals
  • CREB-Binding Protein / drug effects
  • CREB-Binding Protein / metabolism*
  • Conditioning, Psychological / drug effects*
  • Fear / drug effects
  • Hippocampus / drug effects*
  • Male
  • Mice
  • Nicotine / adverse effects
  • Nicotine / metabolism
  • Nicotine / pharmacology*
  • Nicotinic Agonists / adverse effects
  • Nicotinic Agonists / metabolism
  • Nicotinic Agonists / pharmacology*
  • Receptors, Nicotinic / drug effects
  • Receptors, Nicotinic / metabolism*
  • Substance Withdrawal Syndrome / physiopathology*
  • Tobacco Use Disorder
  • Up-Regulation / drug effects


  • Nicotinic Agonists
  • Receptors, Nicotinic
  • Nicotine
  • CREB-Binding Protein
  • Crebbp protein, mouse