Striatal Cholinergic Interneurons Control Physical Nicotine Withdrawal via Muscarinic Receptor Signaling

Abstract Striatal cholinergic interneurons (ChIs) provide acetylcholine tone to the striatum and govern motor functions. Nicotine withdrawal elicits physical symptoms that dysregulate motor behavior. Here, the role of striatal ChIs in physical nicotine withdrawal is investigated. Mice under RNAi‐dependent genetic inhibition of striatal ChIs (ChI ^GI ) by suppressing the sodium channel subunit Na _V 1.1, lessening action potential generation and activity‐dependent acetylcholine release is first generated. ChI ^GI markedly reduced the somatic signs of nicotine withdrawal without affecting other nicotine‐dependent or striatum‐associated behaviors. Multielectrode array (MEA) recording revealed that ChI ^GI reversed ex vivo nicotine‐induced alterations in the number of neural population spikes in the dorsal striatum. Notably, the drug repurposing strategy revealed that a clinically‐approved antimuscarinic drug, procyclidine, fully mimicked the therapeutic electrophysiological effects of ChI ^GI . Furthermore, both ChI ^GI and procyclidine prevented the nicotine withdrawal‐induced reduction in striatal dopamine release in vivo. Lastly, therapeutic intervention with procyclidine dose‐dependently diminished the physical signs of nicotine withdrawal. The data demonstrated that the striatal ChIs are a critical substrate of physical nicotine withdrawal and that muscarinic antagonism holds therapeutic potential against nicotine withdrawal.