Adult-administered chronic nicotine remodels nigral dopaminergic and pedunculopontine cholinergic physiology

Nicotine is linked to neuroprotection and has been proposed as a potential preventative treatment for Parkinson’s disease (PD). Because PD is an aging disorder, such a treatment would necessarily be administered to adults. However, previous studies examining the effects of chronic nicotine in neurons vulnerable to PD have primarily been conducted in juvenile animals. Here we administer chronic nicotine to adult mice of both sexes. We examine nicotine-induced functional adaptations in two brain structures vulnerable to PD, the substantia nigra pars compacta (SNc) and the pedunculopontine nucleus (PPN). Using whole-cell patch-clamp electrophysiology and two-photon calcium imaging, we observed changes in cellular properties that potentially contribute to reduced risk of PD associated with nicotine exposure. Chronic nicotine decreased pacemaking frequency, burst propensity, and rebound firing in SNc dopaminergic neurons, while decoupling tonic firing rate from dendritic calcium levels. These changes in the SNc occurred without altering L-type channel contributions, dendritic arborization, or excitatory synaptic drive. Although the PPN degenerates in PD and is the primary cholinergic input to the SNc, no previous studies have evaluated the effects of chronic nicotine on this structure. We find that chronic nicotine induced subregion-specific plasticity in the PPN. 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. While these PPN alterations do not have a previously established link with cellular vulnerability, synaptic and physiological changes in this region may have unexpected contributions to PD progression. In addition, these findings reveal novel mechanisms that could underlie nicotine’s modulation of brainstem circuitry controlling arousal, sensory gating, and drug dependence.