Kim, Baeksun Kim, Han Ah Woo, Jun Sung Lee, Hyeon-Jeong Kim, Tae Kyoo Min, Ho phil Lee, Chang joon Justin Im, Heh In 2024-11-27T11:30:18Z 2024-11-27T11:30:18Z 2024-11-25 2024-12 https://pubs.kist.re.kr/handle/201004/151146 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 (ChIGI) by suppressing the sodium channel subunit NaV1.1, lessening action potential generation and activity-dependent acetylcholine release is first generated. ChIGI markedly reduced the somatic signs of nicotine withdrawal without affecting other nicotine-dependent or striatum-associated behaviors. Multielectrode array (MEA) recording revealed that ChIGI 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 ChIGI. Furthermore, both ChIGI 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. English Wiley-VCH Verlag Striatal Cholinergic Interneurons Control Physical Nicotine Withdrawal via Muscarinic Receptor Signaling Article 10.1002/advs.202402274 1 Advanced Science, v.11, no.47 Advanced Science 11 47 Y scie scopus 001357298000001 Chemistry, Multidisciplinary Nanoscience & Nanotechnology Materials Science, Multidisciplinary Chemistry Science & Technology - Other Topics Materials Science Article PROJECTION NEURONS DOPAMINE RELEASE ACUTE DEPENDENCE NUCLEUS MODULATION ACTIVATION MORPHINE SMOKING REWARD BRAIN dopamine dorsal striatum muscarinic receptor neural activity nicotine withdrawal somatic signs cholinergic interneurons