Ryanodine receptor-2 upregulation and nicotine-mediated plasticity

Elena Ziviani, Giordano Lippi, Daniele Bano, Eliana Munarriz, Stefania Guiducci, Michele Zoli, Kenneth W. Young, Pierluigi Nicotera

Research output: Contribution to journalArticlepeer-review


Nicotine, the major psychoactive component of cigarette smoke, modulates neuronal activity to produce Ca 2+-dependent changes in gene transcription. However, the downstream targets that underlie the long-term effects of nicotine on neuronal function, and hence behaviour, remain to be elucidated. Here, we demonstrate that nicotine administration to mice upregulates levels of the type 2 ryanodine receptor (RyR2), a Ca 2+-release channel present on the endoplasmic reticulum, in a number of brain areas associated with cognition and addiction, notably the cortex and ventral midbrain. Nicotine-mediated RyR2 upregulation was driven by CREB, and caused a long-lasting reinforcement of Ca 2+ signalling via the process of Ca 2+-induced Ca 2+ release. RyR2 upregulation was itself required for long-term phosphorylation of CREB in a positive-feedback signalling loop. We further demonstrate that inhibition of RyR-activation in vivo abolishes sensitization to nicotine-induced habituated locomotion, a well-characterised model for onset of drug dependence. Our findings, therefore, indicate that gene-dependent reprogramming of Ca 2+ signalling is involved in nicotine-induced behavioural changes.

Original languageEnglish
Pages (from-to)194-204
Number of pages11
JournalEMBO Journal
Issue number1
Publication statusPublished - Jan 5 2011


  • calcium
  • CREB
  • gene expression
  • neuronal plasticity
  • sensitization to locomotor activity

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)


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