A new framework for nicotinic receptor-targeted therapeutic strategies in psychiatric and neurodegenerative disorders

The nicotinic acetylcholine receptors (nAChRs) are key modulators of synaptic transmission and cognitive processing within the central nervous system. These ligand-gated channels, composed of various α and β subunits, mediate a plethora of neuronal functions including attention, memory and executive control. The current perspective article synthesizes recent advances on the contribution of pivotal nAChRs subtypes particularly α4β2, α7, and α5-containing receptors to cortical circuit function, highlighting their relevance in health and disease. In healthy brain, nAChRs regulate excitatory-inhibitory balance and enhance cognitive mechanisms in the prefrontal cortex (PFC) and hippocampus. Recent findings demonstrate that α5-containing receptors exhibit selective resistance to amyloid-β induced dysfunction, suggesting a neuroprotective role in Alzheimer's disease (AD). Integrating molecular, cellular, and behavioral evidence, we argue that receptor-subtype-specific modulation of distinct nAChRs subunits represents a promising therapeutic avenue for restoring network balance and cognitive function across neuropsychiatric and neurodegenerative disorders. We further discuss the role of nicotine in brain circuits and suggest that future research should prioritize precision pharmacology and genetic profiling to identify optimal therapeutic windows and mitigate the long-term consequences of nicotine exposure on developing neural circuits.