{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:36:45Z","timestamp":1790743005218,"version":"4.1.0"},"reference-count":60,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2020,11,24]],"date-time":"2020-11-24T00:00:00Z","timestamp":1606176000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Disorders and Stroke of the National Institutes of Health","award":["R01 NS060803"],"award-info":[{"award-number":["R01 NS060803"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Background: Parkinsonism is caused by dopamine (DA) insufficiency and results in a hypokinetic movement disorder. Treatment with L-Dopa can restore DA availability and improve motor function, but patients can develop L-Dopa-induced dyskinesia (LID), a secondary hyperkinetic movement disorder. The mechanism underlying LID remains unknown, and new treatments are needed. Experiments in mice have shown that DA deficiency promotes an imbalance between striatal acetylcholine (ACh) and DA that contributes to motor dysfunction. While treatment with L-Dopa improves DA availability, it promotes a paradoxical rise in striatal ACh and a further increase in the ACh to DA ratio may promote LID. Methods: We used conditional Slc6a3DTR\/+ mice to model progressive DA deficiency and the \u03b2-adrenergic receptor (\u03b2-AR) antagonist propranolol to limit the activity of striatal cholinergic interneurons (ChIs). DA-deficient mice were treated with L-Dopa and the dopa decarboxylase inhibitor benserazide. LID and motor performance were assessed by rotarod, balance beam, and open field testing. Electrophysiological experiments characterized the effects of \u03b2-AR ligands on striatal ChIs. Results: LID was observed in a subset of DA-deficient mice. Treatment with propranolol relieved LID and motor hyperactivity. Electrophysiological experiments showed that \u03b2-ARs can effectively modulate ChI firing. Conclusions: The work suggests that pharmacological modulation of ChIs by \u03b2-ARs might provide a therapeutic option for managing LID.<\/jats:p>","DOI":"10.3390\/brainsci10120903","type":"journal-article","created":{"date-parts":[[2020,11,24]],"date-time":"2020-11-24T09:06:28Z","timestamp":1606208788000},"page":"903","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Propranolol Relieves L-Dopa-Induced Dyskinesia in Parkinsonian Mice"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9151-8013","authenticated-orcid":false,"given":"Ziqing","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Yale University, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian J.","family":"Bamford","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Yale University, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan W.","family":"McKinley","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Yale University, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suma Priya Sudarsana","family":"Devi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Yale University, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annie","family":"Vahedipour","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Yale University, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3375-1022","authenticated-orcid":false,"given":"Nigel S.","family":"Bamford","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Yale University, New Haven, CT 06510, USA"},{"name":"Departments of Neurology and Cellular and Molecular Physiology, Yale University, New Haven, CT 06510, USA"},{"name":"Department of Neurology, University of Washington, Seattle, WA 98105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1749-6632.2003.tb07458.x","article-title":"Description of Parkinson\u2019s Disease as a Clinical Syndrome","volume":"991","author":"Fahn","year":"2006","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"a008870","DOI":"10.1101\/cshperspect.a008870","article-title":"Clinical approach to parkinson\u2019s disease: Features, diagnosis, and principles of management","volume":"2","author":"Massano","year":"2012","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1002\/mds.21475","article-title":"Levodopa-induced dyskinesias","volume":"22","author":"Fabbrini","year":"2007","journal-title":"Mov. Disord."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e2238","DOI":"10.1212\/WNL.0000000000006643","article-title":"Levodopa-induced dyskinesia in Parkinson disease","volume":"91","author":"Turcano","year":"2018","journal-title":"Neurology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"S263","DOI":"10.1016\/S1353-8020(08)70014-2","article-title":"L-DOPA-induced dyskinesia: Cellular mechanisms and approaches to treatment","volume":"13","author":"Cenci","year":"2007","journal-title":"Park. Relat. Disord."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1002\/mds.25382","article-title":"Levodopa-induced dyskinesias in tyrosine hydroxylase deficiency","volume":"28","author":"Pons","year":"2013","journal-title":"Mov. Disord."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S1353-8020(00)00084-5","article-title":"The long-term response to levodopa in dopa-responsive dystonia","volume":"8","author":"Hwang","year":"2001","journal-title":"Park. Relat. Disord."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1002\/mds.26125","article-title":"Clinical spectrum of levodopa-induced complications","volume":"30","author":"Aquino","year":"2014","journal-title":"Mov. Disord."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"242","DOI":"10.3389\/fneur.2014.00242","article-title":"Presynaptic Mechanisms of l-DOPA-Induced Dyskinesia: The Findings, the Debate, and the Therapeutic Implications","volume":"5","author":"Cenci","year":"2014","journal-title":"Front. Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1016\/j.neuron.2018.01.006","article-title":"Dopamine\u2019s Effects on Corticostriatal Synapses during Reward-Based Behaviors","volume":"97","author":"Bamford","year":"2018","journal-title":"Neuron"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Tseng, K.Y. (2009). The Corticostriatal Pathway in Parkinson\u2019s Disease. Cortico-Subcortical Dynamics in Parkinson\u2019s Disease, Humana Press.","DOI":"10.1007\/978-1-60327-252-0"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1073\/pnas.1006511108","article-title":"Enhanced striatal cholinergic neuronal activity mediates L-DOPA-induced dyskinesia in parkinsonian mice","volume":"108","author":"Ding","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1016\/j.neuron.2019.06.013","article-title":"Dopamine Deficiency Reduces Striatal Cholinergic Interneuron Function in Models of Parkinson\u2019s Disease","volume":"103","author":"McKinley","year":"2019","journal-title":"Neuron"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.nbd.2016.02.019","article-title":"Optogenetic activation of striatal cholinergic interneurons regulates L-dopa-induced dyskinesias","volume":"91","author":"Bordia","year":"2016","journal-title":"Neurobiol. Dis."},{"key":"ref_15","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":"Won","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/0006-8993(82)90615-1","article-title":"Muscarinic binding and choline acetyltransferase activity in Parkinsonian subjects with reference to dementia","volume":"232","author":"Ruberg","year":"1982","journal-title":"Brain Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.1001\/jama.1957.02970500036010","article-title":"Treatment of paralysis agitans with orphenadrine (disipal) hydrochloride; results in one hundred seventy-six cases","volume":"163","author":"Doshay","year":"1957","journal-title":"J. Am. Med. Assoc."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1080\/00325481.1978.11714901","article-title":"Parkinsonism. Clinical and neuropharmacologic aspects","volume":"64","author":"Calne","year":"1978","journal-title":"Postgrad. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1016\/0306-4522(83)90102-1","article-title":"The striatal cholinergic interneuron: Synaptic target of dopaminergic terminals?","volume":"10","author":"Lehmann","year":"1983","journal-title":"Neuroscience"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1016\/S0140-6736(76)93095-6","article-title":"Dopamine acetylcholine imbalance in parkinson\u2019s disease. Possible regenerative overgrowth of cholinergic axon terminals","volume":"1","author":"Spehlmann","year":"1976","journal-title":"Lancet"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1177\/1073858418824256","article-title":"The Striatum\u2019s Role in Executing Rational and Irrational Economic Behaviors","volume":"25","author":"Bamford","year":"2019","journal-title":"Neuroscientist"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1016\/S2352-4642(19)30330-X","article-title":"Localising movement disorders in childhood","volume":"3","author":"Bamford","year":"2019","journal-title":"Lancet Child Adolesc. Health"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"10405","DOI":"10.1523\/JNEUROSCI.0014-13.2013","article-title":"Acetylcholine encodes long-lasting presynaptic plasticity at glutamatergic synapses in the dorsal striatum after repeated amphetamine exposure","volume":"33","author":"Wang","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"22","DOI":"10.3389\/fnsyn.2014.00022","article-title":"Striatal cholinergic interneuron regulation and circuit effects","volume":"6","author":"Lim","year":"2014","journal-title":"Front. Synaptic Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1111\/j.1471-4159.2010.07137.x","article-title":"Beta1-adrenergic receptors activate two distinct signaling pathways in striatal neurons","volume":"116","author":"Meitzen","year":"2011","journal-title":"J. Neurochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5272","DOI":"10.1523\/JNEUROSCI.23-12-05272.2003","article-title":"Activation of beta1-adrenoceptors excites striatal cholinergic interneurons through a camp-dependent, protein kinase-independent pathway","volume":"23","author":"Pisani","year":"2003","journal-title":"J. Neurosci."},{"key":"ref_27","first-page":"805","article-title":"Molecular mechanism of cAMP modulation of HCN pacemaker channels","volume":"411","author":"Wainger","year":"2001","journal-title":"Nat. Cell Biol."},{"key":"ref_28","first-page":"185","article-title":"Stereospecific pharmacokinetics and pharmacodynamics of beta-adrenergic blockers in humans","volume":"4","author":"Mehvar","year":"2001","journal-title":"J. Pharm. Pharm. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.parkreldis.2016.09.004","article-title":"Propranolol therapy for Tardive dyskinesia: A retrospective examination","volume":"32","author":"Armstrong","year":"2016","journal-title":"Park. Relat. Disord."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3684","DOI":"10.4161\/cc.10.21.18042","article-title":"Regulation of beta-adrenergic receptor function: An emphasis on receptor resensitization","volume":"10","author":"Vasudevan","year":"2011","journal-title":"Cell Cycle"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1212\/WNL.46.6.1548","article-title":"Improvement of levodopa-induced dyskinesia by propranolol in parkinson\u2019s disease","volume":"46","author":"Carpentier","year":"1996","journal-title":"Neurology"},{"key":"ref_32","first-page":"189","article-title":"Levodopa-Induced-Dyskinesias Clinical Features, Incidence, Risk Factors, Management and Impact on Quality of Life","volume":"2","author":"Manson","year":"2012","journal-title":"J. Park. Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.expneurol.2015.06.013","article-title":"Relative contributions of severe dopaminergic neuron ablation and dopamine depletion to cognitive impairment","volume":"271","author":"Morgan","year":"2015","journal-title":"Exp. Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1038\/90795","article-title":"Diphtheria toxin receptor\u2013mediated conditional and targeted cell ablation in transgenic mice","volume":"19","author":"Saito","year":"2001","journal-title":"Nat. Biotechnol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/nn.2467","article-title":"A robust and high-throughput Cre reporting and characterization system for the whole mouse brain","volume":"13","author":"Madisen","year":"2010","journal-title":"Nat. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1016\/S0896-6273(04)00265-X","article-title":"Heterosynaptic Dopamine Neurotransmission Selects Sets of Corticostriatal Terminals","volume":"42","author":"Bamford","year":"2004","journal-title":"Neuron"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.neuron.2008.01.033","article-title":"Repeated Exposure to Methamphetamine Causes Long-Lasting Presynaptic Corticostriatal Depression that Is Renormalized with Drug Readministration","volume":"58","author":"Bamford","year":"2008","journal-title":"Neuron"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"9541","DOI":"10.1523\/JNEUROSCI.2891-04.2004","article-title":"Dopamine Modulates Release from Corticostriatal Terminals","volume":"24","author":"Bamford","year":"2004","journal-title":"J. Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.nbd.2016.09.001","article-title":"Validation of an improved scale for rating l-DOPA-induced dyskinesia in the mouse and effects of specific dopamine receptor antagonists","volume":"96","author":"Sebastianutto","year":"2016","journal-title":"Neurobiol. Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1016\/j.neuron.2018.01.017","article-title":"A Subpopulation of Striatal Neurons Mediates Levodopa-Induced Dyskinesia","volume":"97","author":"Girasole","year":"2018","journal-title":"Neuron"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"5586","DOI":"10.1523\/JNEUROSCI.19-13-05586.1999","article-title":"Spontaneous Activity of Neostriatal Cholinergic InterneuronsIn Vitro","volume":"19","author":"Bennett","year":"1999","journal-title":"J. Neurosci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2414","DOI":"10.1523\/JNEUROSCI.5687-08.2009","article-title":"Age-dependent alterations of corticostriatal activity in the YAC128 mouse model of Huntington disease","volume":"29","author":"Joshi","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_43","unstructured":"Paxinos, G., and Franklin, J. (2005). The Mouse Brain in Stereotaxic Coordinates, Academic Press. [2nd ed.]."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"8493","DOI":"10.1523\/JNEUROSCI.20-22-08493.2000","article-title":"Intrinsic Membrane Properties Underlying Spontaneous Tonic Firing in Neostriatal Cholinergic Interneurons","volume":"20","author":"Bennett","year":"2000","journal-title":"J. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"10289","DOI":"10.1523\/JNEUROSCI.2155-04.2004","article-title":"D2 Dopamine Receptor-Mediated Modulation of Voltage-Dependent Na+ Channels Reduces Autonomous Activity in Striatal Cholinergic Interneurons","volume":"24","author":"Maurice","year":"2004","journal-title":"J. Neurosci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.nbd.2004.01.007","article-title":"A model of l-DOPA-induced dyskinesia in 6-hydroxydopamine lesioned mice: Relation to motor and cellular parameters of nigrostriatal function","volume":"16","author":"Lundblad","year":"2004","journal-title":"Neurobiol. Dis."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1111\/jnc.13125","article-title":"Effects of the beta-adrenergic receptor antagonist Propranolol on dyskinesia and L-DOPA-induced striatal DA efflux in the hemi-parkinsonian rat","volume":"134","author":"Bhide","year":"2015","journal-title":"J. Neurochem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1038\/nature05506","article-title":"Endocannabinoid-mediated rescue of striatal ltd and motor deficits in parkinson\u2019s disease models","volume":"445","author":"Kreitzer","year":"2007","journal-title":"Nature"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1016\/0006-8993(87)90022-9","article-title":"Alpha 2-adrenergic receptors mediate inhibition of cyclic amp production in neurons in primary culture","volume":"414","author":"Weiss","year":"1987","journal-title":"Brain Res."},{"key":"ref_50","first-page":"75","article-title":"Recent Advances in Research on Parkinson Disease: Synuclein and Parkin","volume":"10","author":"Burke","year":"2004","journal-title":"Neurology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1124\/jpet.111.179416","article-title":"Behavioral and cellular modulation of L-DOPA-induced dyskinesia by beta-adrenoceptor blockade in the 6-hydroxydopamine-lesioned rat","volume":"337","author":"Lindenbach","year":"2011","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1097\/00002826-199310000-00004","article-title":"Effect of Nondopaminergic Drugs on L-DOPA-Induced Dyskinesias in MPTP-Treated Monkeys","volume":"16","year":"1993","journal-title":"Clin. Neuropharmacol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1016\/j.neuroscience.2015.01.022","article-title":"Dopamine-dependent corticostriatal synaptic filtering regulates sensorimotor behavior","volume":"290","author":"Wong","year":"2015","journal-title":"Neuroscience"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.baga.2016.02.001","article-title":"Striatal dopamine neurotransmission: Regulation of release and uptake","volume":"6","author":"Sulzer","year":"2016","journal-title":"Basal Ganglia"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"17794","DOI":"10.1074\/jbc.M117.800722","article-title":"Mechanism for the inhibition of the cAMP dependence of HCN ion channels by the auxiliary subunit TRIP8b","volume":"292","author":"Bankston","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.neuron.2012.04.038","article-title":"Striatal Dopamine Release Is Triggered by Synchronized Activity in Cholinergic Interneurons","volume":"75","author":"Threlfell","year":"2012","journal-title":"Neuron"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3312","DOI":"10.1523\/JNEUROSCI.4262-04.2005","article-title":"Amantadine Inhibits NMDA Receptors by Accelerating Channel Closure during Channel Block","volume":"25","author":"Blanpied","year":"2005","journal-title":"J. Neurosci."},{"key":"ref_58","first-page":"834","article-title":"Amantadine inhibits nicotinic acetylcholine receptor function in hippocampal neurons","volume":"281","author":"Matsubayashi","year":"1997","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1111\/j.2042-7158.1970.tb10592.x","article-title":"Potentiation by amantadine hydrochloride of L-dopa-induced effects in mice","volume":"22","author":"Svensson","year":"1970","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_60","first-page":"219","article-title":"Chemical management of levodopa-induced dyskinesia in Parkinson\u2019s disease patients","volume":"20","year":"2018","journal-title":"Expert Opin. Pharmacother."}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/10\/12\/903\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:36:47Z","timestamp":1760179007000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/10\/12\/903"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,24]]},"references-count":60,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["brainsci10120903"],"URL":"https:\/\/doi.org\/10.3390\/brainsci10120903","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,24]]}}}