Modulating neuropeptide Y pathways to combat nicotine addiction through emerging evidence and future directions.

Nicotine addiction constitutes a significant global health burden, primarily driven by the substance's capacity to dysregulate the brain's reward and stress systems. This chronic relapsing disorder is characterized by robust dependence and high rates of relapse, underscoring the limitations of current therapeutic strategies. Neuropeptide Y (NPY), a 36-amino acid neuromodulator abundantly expressed in the central nervous system, has emerged as a critical regulator of emotional behavior, stress responses, and reward pathways. Its role in the pathophysiology of nicotine addiction is of increasing interest. NPY exerts its pleiotropic effects via G-protein-coupled receptors (Y1, Y2, and Y5), which are strategically positioned to modulate stress-related circuits and attenuate the hyper-dopaminergic state induced by nicotine in the mesolimbic system. Chronic nicotine exposure disrupts endogenous NPYergic signaling in key neuroanatomical loci such as the amygdala and prefrontal cortex, a neuroadaptation that heightens stress sensitivity and addiction vulnerability. The consequent reduction in NPY tone during withdrawal exacerbates the negative affective states of anxiety and stress, precipitating relapse. Preclinical evidence indicates that therapeutic strategies targeting NPY pathways including receptor-specific agonists, gene therapy for region-specific overexpression, and advanced peptide delivery systems show considerable promise for mitigating withdrawal symptomatology and reducing nicotine-seeking behavior. This review synthesizes the compelling preclinical and emerging human evidence supporting the NPY system as a therapeutic target, highlighting the critical need to develop novel, brain-penetrant NPY receptor agonists and biomarkers to bridge the translational gap and improve clinical outcomes for nicotine dependence.