Nicotine addiction is increasingly understood not as a transient neurotransmitter imbalance but as a chronic neurobiological condition characterized by persistent neuronal and neuro-glial adaptations. Chronic nicotine exposure activates transcriptional and stress-related signaling pathways, including CREB, NF-κB, and JNK, which promote long-lasting synaptic remodeling and stabilization of maladaptive neural circuits. In parallel, astroglial reactivity contributes to maintaining a dysfunctional synaptic environment that reinforces addiction-related brain states.

This model explains why relapse vulnerability often persists after smoking cessation and highlights the limitations of current therapies, which mainly address withdrawal symptoms through nicotinic receptor modulation. The emerging paradigm supports therapeutic strategies targeting the molecular and neuro-glial mechanisms underlying addiction chronicity, with the goal of restoring neuronal plasticity and improving long-term cessation outcomes.

Nicotine activates nicotinic receptors (nAChR), inducing dopamine release and activation of the cAMP/PKA/CREB pathway in postsynaptic neurons. CREB phosphorylation leads to epigenetic and transcriptional changes responsible for lasting neuroadaptations, contributing to the development and maintenance of nicotine addiction.