{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T18:49:34Z","timestamp":1774464574725,"version":"3.50.1"},"reference-count":50,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T00:00:00Z","timestamp":1774396800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000864","name":"Michael J. Fox Foundation for Parkinson's Research","doi-asserted-by":"publisher","award":["MJFF-021787"],"award-info":[{"award-number":["MJFF-021787"]}],"id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    Parkinson\u2019s disease is a neurodegenerative movement disorder which is characterized by cardinal motor symptoms of tremor at rest, rigidity, bradykineasia, and postural instability. Underlying these cardinal motor symptoms is thought to be death and dysfunction of nigrostriatal dopamine neurons, and the gold-standard treatment of Parkinson\u2019s disease is dopamine replacement therapy with the dopamine precursor L-DOPA. While efficacious, L-DOPA does not treat all motor symptoms and can have serious treatment-related side effects called L-DOPA induced dyskinesias, indicating an immense need for new targets to modulate dopaminergic function for anti-parkinsonian efficacy. One such potential target is the M\n                    <jats:sub>5<\/jats:sub>\n                    muscarinic acetylcholine receptor, which has a unique expression profile where it is selectively expressed in midbrain dopaminergic neurons and their terminals in the striatum, and previous studies have indicated that M\n                    <jats:sub>5<\/jats:sub>\n                    can modulate dopamine release and patterning of firing of dopamine neurons. Given this unique expression profile and function of M\n                    <jats:sub>5<\/jats:sub>\n                    , this receptor has an untested potential to modulate parkinsonian motor phenotypes. To test the potential for M\n                    <jats:sub>5<\/jats:sub>\n                    to modulate Parkinsonian-like motor deficits and dyskinesia, we employed the unilateral 6-OHDA lesioned mouse model to create a hemi-parkinsonian state. Using multiple behavioral assays, including the cylinder test, forepaw adjusting steps assay, and in the Erasmus ladder, in conjunction with prototypical M\n                    <jats:sub>5<\/jats:sub>\n                    pharmacological tool compounds, we investigated the ability of M\n                    <jats:sub>5<\/jats:sub>\n                    to modulate parkinsonian motor deficits. Additionally, we tested the ability of M\n                    <jats:sub>5<\/jats:sub>\n                    to modulate established L-DOPA induced dyskinesia or cause dyskinesia on its own. Overall, we found that M\n                    <jats:sub>5<\/jats:sub>\n                    PAM alleviates forepaw asymmetry, bradykinesia, and spatial aspects of gait in the Erasmus ladder. Excitingly, M\n                    <jats:sub>5<\/jats:sub>\n                    PAM does not cause robust dyskinesia, does not affect already established L-DOPA-induced dyskinesia, and does not affect L-DOPA motor efficacy. Taken together with previous findings, the current study suggests that M\n                    <jats:sub>5<\/jats:sub>\n                    receptors are an exciting novel therapeutic strategy for ameliorating parkinsonian motor deficits even in late-stage models of severe PD without lessening L-DOPA\u2019s motor benefit and without affecting existing symptoms of L-DOPA-induced dyskinesia.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0345115","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T17:25:06Z","timestamp":1774459506000},"page":"e0345115","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["M5 positive allosteric modulation alleviates parkinsonian motor deficits"],"prefix":"10.1371","volume":"21","author":[{"given":"Nicole E.","family":"Chambers","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dominic","family":"Hall","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Morgan","family":"Kaplan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah","family":"Garan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tyler","family":"Eichner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8023-1313","authenticated-orcid":true,"given":"Mark S.","family":"Moehle","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2026,3,25]]},"reference":[{"key":"pone.0345115.ref001","article-title":"Update on models of basal ganglia function and dysfunction","author":"M DeLong","year":"2009","journal-title":"Parkinsonism Relat Disord"},{"issue":"3","key":"pone.0345115.ref002","doi-asserted-by":"crossref","first-page":"315","DOI":"10.31887\/DCNS.2004.6.3\/akorczyn","article-title":"Drug treatment of Parkinson\u2019s disease","volume":"6","author":"AD Korczyn","year":"2004","journal-title":"Dialogues Clin Neurosci"},{"issue":"3","key":"pone.0345115.ref003","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1002\/ana.410240304","article-title":"Motor fluctuations in Parkinson\u2019s disease: central pathophysiological mechanisms, Part II","volume":"24","author":"MM Mouradian","year":"1988","journal-title":"Ann Neurol"},{"key":"pone.0345115.ref004","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.parkreldis.2016.07.006","article-title":"Pharmacological treatment in Parkinson\u2019s disease: effects on gait","volume":"31","author":"K Smulders","year":"2016","journal-title":"Parkinsonism Relat Disord"},{"issue":"3","key":"pone.0345115.ref005","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1002\/mds.1090","article-title":"Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature","volume":"16","author":"JE Ahlskog","year":"2001","journal-title":"Mov Disord"},{"issue":"2","key":"pone.0345115.ref006","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1042\/BST20220525","article-title":"The muscarinic M4 acetylcholine receptor exacerbates symptoms of movement disorders","volume":"51","author":"NE Chambers","year":"2023","journal-title":"Biochem Soc Trans"},{"issue":"6","key":"pone.0345115.ref007","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1016\/j.neuron.2017.12.008","article-title":"Cholinergic Projections to the substantia Nigra Pars reticulata inhibit dopamine modulation of basal ganglia through the M4 muscarinic receptor","volume":"96","author":"MS Moehle","year":"2017","journal-title":"Neuron"},{"issue":"47","key":"pone.0345115.ref008","doi-asserted-by":"crossref","DOI":"10.1126\/sciadv.adp6301","article-title":"Reduced striatal M4-cholinergic signaling following dopamine loss contributes to parkinsonian and l-DOPA-induced dyskinetic behaviors","volume":"10","author":"BE Nielsen","year":"2024","journal-title":"Sci Adv"},{"key":"pone.0345115.ref009","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/s13024-015-0044-5","article-title":"Pharmacogenetic stimulation of cholinergic pedunculopontine neurons reverses motor deficits in a rat model of Parkinson\u2019s disease","volume":"10","author":"IS Pienaar","year":"2015","journal-title":"Mol Neurodegener"},{"issue":"4","key":"pone.0345115.ref010","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1016\/j.neuron.2015.10.039","article-title":"M4 muscarinic receptor signaling ameliorates striatal plasticity deficits in models of L-DOPA-induced dyskinesia","volume":"88","author":"W Shen","year":"2015","journal-title":"Neuron"},{"issue":"8","key":"pone.0345115.ref011","doi-asserted-by":"crossref","first-page":"3090","DOI":"10.1523\/JNEUROSCI.2888-13.2014","article-title":"Striatal cholinergic cell ablation attenuates L-DOPA induced dyskinesia in Parkinsonian mice","volume":"34","author":"L Won","year":"2014","journal-title":"J Neurosci"},{"key":"pone.0345115.ref012","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/S0079-6123(08)62388-2","article-title":"Muscarinic acetylcholine receptor subtypes: localization and structure\/function","volume":"98","author":"MR Brann","year":"1993","journal-title":"Prog Brain Res"},{"key":"pone.0345115.ref013","author":"K Bickham","year":"2022","journal-title":"Sub-type selective muscarinic acetylcholine receptors modulation for the treatment of parkinsonian tremor"},{"issue":"12","key":"pone.0345115.ref014","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.1007\/s00702-024-02799-7","article-title":"Anticholinergic drugs for parkinsonism and other movement disorders","volume":"131","author":"PA LeWitt","year":"2024","journal-title":"J Neural Transm (Vienna)"},{"issue":"4","key":"pone.0345115.ref015","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.1021\/acsptsci.0c00162","article-title":"Discovery of the first selective M4 muscarinic acetylcholine receptor antagonists with in vivo antiparkinsonian and antidystonic efficacy","volume":"4","author":"MS Moehle","year":"2021","journal-title":"ACS Pharmacol Transl Sci"},{"issue":"8","key":"pone.0345115.ref016","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1002\/mds.27740","article-title":"Roles of the M4 acetylcholine receptor in the basal ganglia and the treatment of movement disorders","volume":"34","author":"MS Moehle","year":"2019","journal-title":"Mov Disord"},{"key":"pone.0345115.ref017","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/S0079-6123(08)60922-X","article-title":"Antimuscarinic drugs in the treatment of movement disorders","volume":"84","author":"S Fahn","year":"1990","journal-title":"Prog Brain Res"},{"key":"pone.0345115.ref018","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.nbd.2019.01.012","article-title":"Trihexyphenidyl rescues the deficit in dopamine neurotransmission in a mouse model of DYT1 dystonia","volume":"125","author":"AM Downs","year":"2019","journal-title":"Neurobiol Dis"},{"key":"pone.0345115.ref019","doi-asserted-by":"crossref","first-page":"105699","DOI":"10.1016\/j.nbd.2022.105699","article-title":"Blockade of M4 muscarinic receptors on striatal cholinergic interneurons normalizes striatal dopamine release in a mouse model of TOR1A dystonia","volume":"168","author":"AM Downs","year":"2022","journal-title":"Neurobiol Dis"},{"key":"pone.0345115.ref020","doi-asserted-by":"crossref","DOI":"10.1096\/fasebj.2022.36.S1.L8009","article-title":"Development of novel M4 muscarinic acetylcholine receptor antagonists for the treatment of movement disorders","volume":"36","author":"J Rook","year":"2022","journal-title":"FASEB J"},{"issue":"2","key":"pone.0345115.ref021","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/0304-3940(90)90064-G","article-title":"Localization of m5 muscarinic receptor mRNA in rat brain examined by in situ hybridization histochemistry","volume":"114","author":"MT Vilar\u00f3","year":"1990","journal-title":"Neurosci Lett"},{"issue":"18","key":"pone.0345115.ref022","doi-asserted-by":"crossref","first-page":"7050","DOI":"10.1073\/pnas.87.18.7050","article-title":"Expression of muscarinic acetylcholine and dopamine receptor mRNAs in rat basal ganglia","volume":"87","author":"DM Weiner","year":"1990","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"16","key":"pone.0345115.ref023","doi-asserted-by":"crossref","DOI":"10.1523\/JNEUROSCI.1443-24.2025","article-title":"Muscarinic receptor activation preferentially inhibits rebound in vulnerable dopaminergic neurons","volume":"45","author":"ML Beaver","year":"2025","journal-title":"J Neurosci"},{"issue":"9","key":"pone.0345115.ref024","doi-asserted-by":"crossref","first-page":"3253","DOI":"10.1523\/JNEUROSCI.4896-13.2014","article-title":"M5 receptor activation produces opposing physiological outcomes in dopamine neurons depending on the receptor\u2019s location","volume":"34","author":"DJ Foster","year":"2014","journal-title":"J Neurosci"},{"issue":"15","key":"pone.0345115.ref025","doi-asserted-by":"crossref","first-page":"6347","DOI":"10.1523\/JNEUROSCI.22-15-06347.2002","article-title":"Multiple muscarinic acetylcholine receptor subtypes modulate striatal dopamine release, as studied with M1-M5 muscarinic receptor knock-out mice","volume":"22","author":"W Zhang","year":"2002","journal-title":"J Neurosci"},{"issue":"17","key":"pone.0345115.ref026","doi-asserted-by":"crossref","first-page":"11452","DOI":"10.1073\/pnas.162371899","article-title":"Deletion of the M5 muscarinic acetylcholine receptor attenuates morphine reinforcement and withdrawal but not morphine analgesia","volume":"99","author":"AS Basile","year":"2002","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"7","key":"pone.0345115.ref027","doi-asserted-by":"crossref","first-page":"1510","DOI":"10.1038\/s41386-017-0007-3","article-title":"Muscarinic M5 receptors modulate ethanol seeking in rats","volume":"43","author":"AE Berizzi","year":"2018","journal-title":"Neuropsychopharmacology"},{"issue":"8","key":"pone.0345115.ref028","doi-asserted-by":"crossref","first-page":"3740","DOI":"10.1021\/acschemneuro.9b00274","article-title":"Acute negative allosteric modulation of M5 muscarinic acetylcholine receptors inhibits oxycodone self-administration and cue-induced reactivity with no effect on antinociception","volume":"10","author":"RW Gould","year":"2019","journal-title":"ACS Chem Neurosci"},{"key":"pone.0345115.ref029","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.neuroscience.2019.04.008","article-title":"Effects of muscarinic acetylcholine m1 and m4 receptor blockade on dyskinesia in the Hemi-Parkinsonian rat","volume":"409","author":"NE Chambers","year":"2019","journal-title":"Neuroscience"},{"issue":"8","key":"pone.0345115.ref030","doi-asserted-by":"crossref","first-page":"2835","DOI":"10.1111\/ejn.15106","article-title":"Effects of pedunculopontine nucleus cholinergic lesion on gait and dyskinesia in hemiparkinsonian rats","volume":"53","author":"NE Chambers","year":"2021","journal-title":"Eur J Neurosci"},{"issue":"22","key":"pone.0345115.ref031","doi-asserted-by":"crossref","first-page":"9351","DOI":"10.1021\/jm4013246","article-title":"Discovery of the First M5-Selective and CNS Penetrant Negative Allosteric Modulator (NAM) of a Muscarinic Acetylcholine Receptor: (S)-9b-(4-Chlorophenyl)-1-(3,4-difluorobenzoyl)-2,3-dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-one (ML375)","volume":"56","author":"PR Gentry","year":"2013","journal-title":"J Med Chem"},{"issue":"11","key":"pone.0345115.ref032","doi-asserted-by":"crossref","first-page":"3445","DOI":"10.1021\/jm900286j","article-title":"Discovery of the first highly M5-preferring muscarinic acetylcholine receptor ligand, an M5 positive allosteric modulator derived from a series of 5-trifluoromethoxy N-benzyl isatins","volume":"52","author":"TM Bridges","year":"2009","journal-title":"J Med Chem"},{"issue":"1","key":"pone.0345115.ref033","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1046\/j.0953-816x.2001.01843.x","article-title":"Pharmacological validation of behavioural measures of akinesia and dyskinesia in a rat model of Parkinson\u2019s disease","volume":"15","author":"M Lundblad","year":"2002","journal-title":"Eur J Neurosci"},{"issue":"5","key":"pone.0345115.ref034","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1016\/S0028-3908(00)00005-8","article-title":"CNS plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, parkinsonism and spinal cord injury","volume":"39","author":"T Schallert","year":"2000","journal-title":"Neuropharmacology"},{"issue":"12","key":"pone.0345115.ref035","doi-asserted-by":"crossref","first-page":"4686","DOI":"10.1523\/JNEUROSCI.20-12-04686.2000","article-title":"Long-term rAAV-mediated gene transfer of GDNF in the rat Parkinson\u2019s model: intrastriatal but not intranigral transduction promotes functional regeneration in the lesioned nigrostriatal system","volume":"20","author":"D Kirik","year":"2000","journal-title":"J Neurosci"},{"issue":"2","key":"pone.0345115.ref036","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/S0306-4522(98)00217-6","article-title":"Biochemical and anatomical characterization of forepaw adjusting steps in rat models of Parkinson\u2019s disease: studies on medial forebrain bundle and striatal lesions","volume":"88","author":"JW Chang","year":"1999","journal-title":"Neuroscience"},{"key":"pone.0345115.ref037","doi-asserted-by":"crossref","first-page":"106861","DOI":"10.1016\/j.nlm.2018.04.016","article-title":"Cerebellar contribution to locomotor behavior: a neurodevelopmental perspective","volume":"165","author":"A Sathyanesan","year":"2019","journal-title":"Neurobiol Learn Mem"},{"key":"pone.0345115.ref038","article-title":"Monitoring fine and associative motor learning in mice using the Erasmus ladder","volume":"202","author":"A Staffa","year":"2023","journal-title":"J Vis Exp"},{"key":"pone.0345115.ref039","doi-asserted-by":"crossref","DOI":"10.1002\/0471142301.ns0925s41","article-title":"Ratings of L-DOPA-induced dyskinesia in the unilateral 6-OHDA lesion model of Parkinson\u2019s disease in rats and mice","volume-title":"Curr Protoc Neurosci","author":"MA Cenci","year":"2007"},{"issue":"7","key":"pone.0345115.ref040","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1038\/nrn877","article-title":"Animal models of neurological deficits: how relevant is the rat?","volume":"3","author":"MA Cenci","year":"2002","journal-title":"Nat Rev Neurosci"},{"issue":"2","key":"pone.0345115.ref041","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1006\/nbdi.2002.0499","article-title":"L-DOPA-induced dyskinesia in the intrastriatal 6-hydroxydopamine model of parkinson\u2019s disease: relation to motor and cellular parameters of nigrostriatal function","volume":"10","author":"C Winkler","year":"2002","journal-title":"Neurobiol Dis"},{"issue":"1","key":"pone.0345115.ref042","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1124\/jpet.107.126219","article-title":"Evaluation of levodopa dose and magnitude of dopamine depletion as risk factors for levodopa-induced dyskinesia in a rat model of Parkinson\u2019s disease","volume":"323","author":"DB Putterman","year":"2007","journal-title":"J Pharmacol Exp Ther"},{"key":"pone.0345115.ref043","doi-asserted-by":"crossref","first-page":"16001","DOI":"10.1038\/npjparkd.2016.1","article-title":"Deficits in cholinergic neurotransmission and their clinical correlates in Parkinson\u2019s disease","volume":"2","author":"S Perez-Lloret","year":"2016","journal-title":"NPJ Parkinsons Dis"},{"issue":"35","key":"pone.0345115.ref044","doi-asserted-by":"crossref","first-page":"9161","DOI":"10.1523\/JNEUROSCI.0873-16.2016","article-title":"Involvement of striatal cholinergic interneurons and M1 and M4 muscarinic receptors in motor symptoms of Parkinson\u2019s Disease","volume":"36","author":"S Ztaou","year":"2016","journal-title":"J Neurosci"},{"issue":"7","key":"pone.0345115.ref045","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1097\/00004647-199907000-00010","article-title":"Functional acetylcholine muscarinic receptor subtypes in human brain microcirculation: identification and cellular localization","volume":"19","author":"A Elhusseiny","year":"1999","journal-title":"J Cereb Blood Flow Metab"},{"key":"pone.0345115.ref046","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/S0165-1838(96)00114-2","article-title":"Variation in mRNA expression of alpha-adrenergic, neurokinin and muscarinic receptors amongst four arteries of the rat","volume":"62","author":"JK Phillips","year":"1997","journal-title":"J Auton Nerv Syst"},{"issue":"24","key":"pone.0345115.ref047","doi-asserted-by":"crossref","first-page":"14096","DOI":"10.1073\/pnas.251542998","article-title":"Cholinergic dilation of cerebral blood vessels is abolished in M(5) muscarinic acetylcholine receptor knockout mice","volume":"98","author":"M Yamada","year":"2001","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"5","key":"pone.0345115.ref048","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1111\/adb.12567","article-title":"Selective inhibition of M5 muscarinic acetylcholine receptors attenuates cocaine self-administration in rats","volume":"23","author":"BW Gunter","year":"2018","journal-title":"Addict Biol"},{"issue":"1","key":"pone.0345115.ref049","first-page":"37","article-title":"Side effects of a dopamine agonist therapy for Parkinson\u2019s disease: a mini-review of clinical pharmacology","volume":"89","author":"JA Borovac","year":"2016","journal-title":"Yale J Biol Med"},{"key":"pone.0345115.ref050","first-page":"100091","article-title":"Impact of behavioral side effects on the management of Parkinson patients treated with dopamine agonists","volume":"4","author":"ME Mohammad","year":"2021","journal-title":"Clin Park Relat Disord"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0345115","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T17:25:13Z","timestamp":1774459513000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0345115"}},"subtitle":[],"editor":[{"given":"Bobby","family":"Thomas","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2026,3,25]]},"references-count":50,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,3,25]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0345115","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,25]]}}}