Ryanodine receptor-2 upregulation and nicotine-mediated plasticity

Nicotine, the major psychoactive component of cigarette smoke, modulates neuronal activity to produce Ca²⁺-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 Ca²⁺-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 Ca²⁺²⁺-induced Ca²⁺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 Ca²⁺ signalling via the process of Ca 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 signalling is involved in nicotine-induced behavioural changes.

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