Molecular mechanisms of nicotinic acetylcholine receptors in mood dysregulation

Mood disorders are complex neurobiological disorders in which cholinergic signaling plays a key role in modulating affective states. Nicotinic acetylcholine receptors (nAChRs) of the α4β2 and α7 subtypes modulate neurotransmitter action in circuits associated with mood, synaptic plasticity, and neuroimmune interactions, particularly through microglial and astrocytic pathways. Here, we present an integrative review that accounts for the structural diversity, distribution, and functional roles of nAChRs within the central nervous system (CNS), with particular emphasis on their modulatory effects on monoaminergic, glutamatergic, and GABAergic pathways. We discuss the molecular mechanisms through which nAChRs modulate mood, including calcium-dependent signaling cascades, control of neuroinflammation, modulation of oxidative stress, and epigenetic regulation of receptor expression. Both preclinical and clinical studies have shown that nAChRs play a dual role in mood regulation and demonstrate their potential as pharmacological targets for depression and anxiety. Additionally, we discuss the translational issues and opportunities of subtype-selective ligands, epigenetic interventions, and biomarker-guided treatment approaches. Neuroimaging of nAChRs coupled with precise pharmacology could provide new options for treating psychiatric illnesses.