Chronic nicotine reduces nigral dopaminergic activity and remodels pedunculopontine cholinergic subpopulations

Chronic nicotine is linked to neuroprotective effects and reduced Parkinson's disease (PD) risk, yet its physiological effects on vulnerable substantia nigra pars compacta (SNc) dopaminergic and pedunculopontine nucleus (PPN) cholinergic neurons are not fully understood. These populations exhibit specialized properties such as spontaneous pacemaking and elevated dendritic calcium influx that contribute to their selective neurodegeneration in PD. Here, we used whole-cell patch-clamp, two-photon calcium imaging, and morphological reconstruction in acute brain slices from adult mice of both sexes following 8-10 weeks of oral nicotine. Chronic nicotine reduced spontaneous pacemaking, burst propensity, and rebound firing in SNc dopaminergic neurons, while decoupling tonic firing rate from proximal dendritic calcium levels. The changes in the SNc occurred without altering L-type channel contributions, dendritic arborization, or excitatory synaptic drive. In PPN cholinergic neurons, chronic nicotine induced subregion-specific plasticity. Rostral PPN neurons showed depolarized membrane potentials, broadened action potentials, and dendritic pruning, whereas caudal PPN neurons showed reduced spike frequency adaptation and accelerated excitatory postsynaptic current kinetics. These findings reveal potential cellular and circuit mechanisms by which nicotine may contribute to resilience against PD.