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‐dep...
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Wiley
2024-12-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202402274 |
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| author | Baeksun Kim Han Ah Kim Junsung Woo Hyeon‐Jeong Lee Tae Kyoo Kim Hophil Min C. Justin Lee Heh‐In Im |
| author_facet | Baeksun Kim Han Ah Kim Junsung Woo Hyeon‐Jeong Lee Tae Kyoo Kim Hophil Min C. Justin Lee Heh‐In Im |
| author_sort | Baeksun Kim |
| collection | DOAJ |
| description | 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 (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. |
| format | Article |
| id | doaj-art-b40d567a972c4b5eb320a766c48d18b8 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-b40d567a972c4b5eb320a766c48d18b82024-12-18T14:18:10ZengWileyAdvanced Science2198-38442024-12-011147n/an/a10.1002/advs.202402274Striatal Cholinergic Interneurons Control Physical Nicotine Withdrawal via Muscarinic Receptor SignalingBaeksun Kim0Han Ah Kim1Junsung Woo2Hyeon‐Jeong Lee3Tae Kyoo Kim4Hophil Min5C. Justin Lee6Heh‐In Im7Center for Brain Function Brain Science Institute Korea Institute of Science and Technology (KIST) Seoul 02792 Republic of KoreaCenter for Brain Function Brain Science Institute Korea Institute of Science and Technology (KIST) Seoul 02792 Republic of KoreaCenter for Glia‐Neuron Interaction Brain Science Institute KIST Seoul 02792 Republic of KoreaDoping Control Center KIST Seoul 02792 Republic of KoreaCenter for Brain Function Brain Science Institute Korea Institute of Science and Technology (KIST) Seoul 02792 Republic of KoreaDivision of Bio‐Medical Science & Technology KIST School Korea National University of Science and Technology (UST) Seoul 02792 Republic of KoreaCenter for Glia‐Neuron Interaction Brain Science Institute KIST Seoul 02792 Republic of KoreaCenter for Brain Function Brain Science Institute Korea Institute of Science and Technology (KIST) Seoul 02792 Republic of KoreaAbstract 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.https://doi.org/10.1002/advs.202402274cholinergic interneuronsdopaminedorsal striatummuscarinic receptorneural activitynicotine withdrawal |
| spellingShingle | Baeksun Kim Han Ah Kim Junsung Woo Hyeon‐Jeong Lee Tae Kyoo Kim Hophil Min C. Justin Lee Heh‐In Im Striatal Cholinergic Interneurons Control Physical Nicotine Withdrawal via Muscarinic Receptor Signaling Advanced Science cholinergic interneurons dopamine dorsal striatum muscarinic receptor neural activity nicotine withdrawal |
| title | Striatal Cholinergic Interneurons Control Physical Nicotine Withdrawal via Muscarinic Receptor Signaling |
| title_full | Striatal Cholinergic Interneurons Control Physical Nicotine Withdrawal via Muscarinic Receptor Signaling |
| title_fullStr | Striatal Cholinergic Interneurons Control Physical Nicotine Withdrawal via Muscarinic Receptor Signaling |
| title_full_unstemmed | Striatal Cholinergic Interneurons Control Physical Nicotine Withdrawal via Muscarinic Receptor Signaling |
| title_short | Striatal Cholinergic Interneurons Control Physical Nicotine Withdrawal via Muscarinic Receptor Signaling |
| title_sort | striatal cholinergic interneurons control physical nicotine withdrawal via muscarinic receptor signaling |
| topic | cholinergic interneurons dopamine dorsal striatum muscarinic receptor neural activity nicotine withdrawal |
| url | https://doi.org/10.1002/advs.202402274 |
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