{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T03:58:27Z","timestamp":1776916707466,"version":"3.51.2"},"reference-count":61,"publisher":"Wiley","issue":"17","license":[{"start":{"date-parts":[[2024,4,30]],"date-time":"2024-04-30T00:00:00Z","timestamp":1714435200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["NS108722"],"award-info":[{"award-number":["NS108722"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["NS125519"],"award-info":[{"award-number":["NS125519"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2024,9]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Current pharmacotherapies for Tourette syndrome (TS) are often unsatisfactory and poorly tolerated, underscoring the need for novel treatments. Insufficient striatal acetylcholine has been suggested to contribute to tic ontogeny. Thus, we tested whether activating M<jats:sub>1<\/jats:sub> and\/or M<jats:sub>4<\/jats:sub> receptors\u2014the two most abundant muscarinic receptors in the striatum\u2014reduced tic\u2010related behaviours in mouse models of TS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Studies were conducted using CIN\u2010d and D1CT\u20107 mice, two TS models characterized by early\u2010life depletion of striatal cholinergic interneurons and cortical neuropotentiation, respectively. First, we tested the effects of systemic and intrastriatal xanomeline, a selective M<jats:sub>1<\/jats:sub>\/M<jats:sub>4<\/jats:sub> receptor agonist, on tic\u2010like and other TS\u2010related responses. Then, we examined whether xanomeline effects were reduced by either M<jats:sub>1<\/jats:sub> or M<jats:sub>4<\/jats:sub> antagonists or mimicked by the M<jats:sub>1<\/jats:sub>\/M<jats:sub>3<\/jats:sub> agonist cevimeline or the M<jats:sub>4<\/jats:sub> positive allosteric modulator (PAM) VU0467154. Finally, we measured striatal levels of M<jats:sub>1<\/jats:sub> and M<jats:sub>4<\/jats:sub> receptors and assessed the impact of VU0461754 on the striatal expression of the neural marker activity c\u2010Fos.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Systemic and intrastriatal xanomeline reduced TS\u2010related behaviours in CIN\u2010d and D1CT\u20107 mice. Most effects were blocked by M<jats:sub>4<\/jats:sub>, but not M<jats:sub>1<\/jats:sub>, receptor antagonists. VU0467154, but not cevimeline, elicited xanomeline\u2010like ameliorative effects in both models. M<jats:sub>4<\/jats:sub>, but not M<jats:sub>1<\/jats:sub>, receptors were down\u2010regulated in the striatum of CIN\u2010d mice. Additionally, VU0467154 reduced striatal c\u2010Fos levels in these animals.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Activation of striatal M<jats:sub>4<\/jats:sub>, but not M<jats:sub>1<\/jats:sub>, receptors reduced tic\u2010like manifestations in mouse models, pointing to xanomeline and M<jats:sub>4<\/jats:sub> PAMs as novel putative therapeutic strategies for TS.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.16392","type":"journal-article","created":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T03:22:19Z","timestamp":1714533739000},"page":"3064-3081","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Activation of M<sub>4<\/sub> muscarinic receptors in the striatum reduces tic\u2010like behaviours in two distinct murine models of Tourette syndrome"],"prefix":"10.1111","volume":"181","author":[{"given":"Roberto","family":"Cadeddu","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy University of Utah  Salt Lake City Utah USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giulia","family":"Braccagni","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy University of Utah  Salt Lake City Utah USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caterina","family":"Branca","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy University of Utah  Salt Lake City Utah USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Easton R.","family":"van Luik","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy University of Utah  Salt Lake City Utah USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2117-9321","authenticated-orcid":false,"given":"Christopher","family":"Pittenger","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, School of Medicine Yale University  New Haven Connecticut USA"},{"name":"Department of Psychology, School of Arts and Sciences Yale University  New Haven Connecticut USA"},{"name":"Child Study Center, School of Medicine Yale University  New Haven Connecticut USA"},{"name":"Center for Brain and Mind Health, School of Medicine Yale University  New Haven Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Morten Sk\u00f8tt","family":"Thomsen","sequence":"additional","affiliation":[{"name":"Neuroscience Research, H. 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