{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T18:32:50Z","timestamp":1791484370053,"version":"4.3.4"},"reference-count":79,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2024,7,22]],"date-time":"2024-07-22T00:00:00Z","timestamp":1721606400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Mochida Pharmaceutical Company, Ltd."},{"name":"EuMentis Therapeutics, Inc."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: Tourette syndrome is a neurodevelopmental movement disorder involving basal ganglia dysfunction. PDE10A inhibitors modulate signaling in the striatal basal ganglia nuclei and are thus of interest as potential therapeutics in treating Tourette syndrome and other movement disorders. Methods: The preclinical pharmacology and toxicology, human safety and tolerability, and human PET striatal enzyme occupancy data for the PDE10A inhibitor EM-221 are presented. Results: EM-221 inhibited PDE10A with an in vitro IC50 of 9 pM and was &gt;100,000 selective vs. other PDEs and other CNS receptors and enzymes. In rats, at doses of 0.05\u20130.50 mg\/kg, EM-221 reduced hyperlocomotion and the disruption of prepulse inhibition induced by MK-801, attenuated conditioned avoidance, and facilitated novel object recognition, consistent with PDE10A\u2019s inhibition. EM-221 displayed no genotoxicity and was well tolerated up to 300 mg\/kg in rats and 100 mg\/kg in dogs. In single- and multiple-day ascending dose studies in healthy human volunteers, EM-221 was well tolerated up to 10 mg, with a maximum tolerated dose of 15 mg. PET imaging indicated that a PDE10A enzyme occupancy of up to 92.8% was achieved with a ~24 h half-life. Conclusions: The preclinical and clinical data presented here support the study of EM-221 in phase 2 trials of Tourette syndrome and other movement disorders.<\/jats:p>","DOI":"10.3390\/cells13141230","type":"journal-article","created":{"date-parts":[[2024,7,22]],"date-time":"2024-07-22T08:24:59Z","timestamp":1721636699000},"page":"1230","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["A Novel PDE10A Inhibitor for Tourette Syndrome and Other Movement Disorders"],"prefix":"10.3390","volume":"13","author":[{"given":"Randall D.","family":"Marshall","sequence":"first","affiliation":[{"name":"EuMentis Therapeutics Inc., 275 Grove Street, 2-400, Newton, MA 02466, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2612-9534","authenticated-orcid":false,"given":"Frank S.","family":"Menniti","sequence":"additional","affiliation":[{"name":"MindImmune Therapeutics, Inc., Kingston, RI 02881, USA"},{"name":"The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI 02881, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A.","family":"Tepper","sequence":"additional","affiliation":[{"name":"EuMentis Therapeutics Inc., 275 Grove Street, 2-400, Newton, MA 02466, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/S1474-4422(22)00303-9","article-title":"Tourette syndrome: Clinical features, pathophysiology, and treatment","volume":"22","author":"Johnson","year":"2023","journal-title":"Lancet Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"12387","DOI":"10.1523\/JNEUROSCI.0150-11.2011","article-title":"Neurobiology of Tourette syndrome: Current status and need for further investigation","volume":"31","author":"Felling","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1177\/0883073819867245","article-title":"Predictors of the clinical course of Tourette syndrome: A longitudinal study","volume":"34","author":"Groth","year":"2019","journal-title":"J. Child. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"114684","DOI":"10.1016\/j.psychres.2022.114684","article-title":"Estimating the number of people with Tourette syndrome and persistent tic disorder in the United States","volume":"314","author":"Tinker","year":"2022","journal-title":"Psychiatry Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.pediatrneurol.2012.05.002","article-title":"Prevalence of tic disorders: A systematic review and meta-analysis","volume":"47","author":"Knight","year":"2012","journal-title":"Pediatr. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.15585\/mmwr.su7102a1","article-title":"Mental health surveillance among children\u2014United States, 2013\u20132019","volume":"71","author":"Bitsko","year":"2022","journal-title":"MMWR Suppl."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1001\/jamapsychiatry.2014.2650","article-title":"Lifetime Prevalence, Age of Risk, and Genetic Relationships of Comorbid Psychiatric Disorders in Tourette Syndrome","volume":"72","author":"Hirschtritt","year":"2015","journal-title":"JAMA Psychiatry"},{"key":"ref_8","first-page":"99","article-title":"Neurobiology of basal ganglia and Tourette syndrome: Striatal and dopamine function","volume":"99","author":"Albin","year":"2006","journal-title":"Adv. Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1016\/j.neubiorev.2012.11.004","article-title":"The functional anatomy of Gilles de la Tourette syndrome","volume":"37","author":"Ganos","year":"2013","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"R509","DOI":"10.1016\/S0960-9822(00)00593-5","article-title":"The basal ganglia","volume":"10","author":"Graybiel","year":"2000","journal-title":"Curr. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1001\/archneur.64.1.20","article-title":"Circuits and Circuit Disorders of the Basal Ganglia","volume":"64","author":"DeLong","year":"2007","journal-title":"Arch. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/0166-2236(89)90074-X","article-title":"The functional anatomy of basal ganglia disorders","volume":"12","author":"Albin","year":"1989","journal-title":"Trends Neurosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1038\/nn.3743","article-title":"Direct and indirect pathways of basal ganglia: A critical reappraisal","volume":"17","author":"Calabresi","year":"2014","journal-title":"Nat. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1016\/S0959-4388(96)80024-9","article-title":"and M.R. DeLong, Functional and pathophysiological models of the basal ganglia","volume":"6","author":"Wichmann","year":"1996","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.tins.2007.03.008","article-title":"D1 and D2 dopamine-receptor modulation of striatal glutamatergic signaling in striatal medium spiny neurons","volume":"30","author":"Surmeier","year":"2007","journal-title":"Trends Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1523\/JNEUROSCI.3833-10.2011","article-title":"Functional Connectome of the Striatal Medium Spiny Neuron","volume":"31","author":"Nao","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1006\/nlme.1998.3843","article-title":"The basal ganglia and chunking of action repertoires","volume":"70","author":"Graybiel","year":"1998","journal-title":"Neurobiol. Learn. Mem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"106765","DOI":"10.1016\/j.isci.2023.106765","article-title":"Emergence of rhythmic chunking in complex stepping of mice","volume":"26","author":"Hirokane","year":"2023","journal-title":"Iscience"},{"key":"ref_19","unstructured":"Martino, D., and Cavanna, A.E. (2013). Chapter Five\u2014Reinforcement Learning and Tourette Syndrome. International Review of Neurobiology, Academic Press."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"255","DOI":"10.3109\/00207458908986238","article-title":"Brain Reward Systems and Tourette\u2019s Syndrome","volume":"45","author":"Sandyk","year":"1989","journal-title":"Int. J. Neurosci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/j.braindev.2020.06.003","article-title":"Sensory hypersensitivity in Tourette syndrome: A review","volume":"42","author":"Isaacs","year":"2020","journal-title":"Brain Dev."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Kleimaker, A., Kleimaker, M., B\u00e4umer, T., Beste, C., and M\u00fcnchau, A. (2020). Gilles de la Tourette Syndrome\u2014A Disorder of Action-Perception Integration. Front. Neurol., 11.","DOI":"10.3389\/fneur.2020.597898"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"95","DOI":"10.2147\/NDT.S12990","article-title":"Update on the role of antipsychotics in the treatment of Tourette syndrome","volume":"8","author":"Huys","year":"2012","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1007\/s40263-018-0559-8","article-title":"Antipsychotic-associated symptoms of tourette syndrome: A systematic review","volume":"32","author":"Kim","year":"2018","journal-title":"CNS Drugs"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Charych, E.I., and Brandon, N.J. (2014). Molecular and Cellular Understanding of PDE10A: A Dual-Substrate Phosphodiesterase with Therapeutic Potential to Modulate Basal Ganglia Function. Cyclic-Nucleotide Phosphodiesterases in the Central Nervous System, John Wiley & Sons, Inc.","DOI":"10.1002\/9781118836507.ch10"},{"key":"ref_26","first-page":"458","article-title":"PDE10A Inhibitors: An Assessment of the Current CNS Drug Discovery Landscape","volume":"12","author":"Chappie","year":"2009","journal-title":"Curr. Opin. Investig. Drugs"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Menniti, F.S., Chappie, T.A., and Schmidt, C.J. (2021). PDE10A inhibitors\u2014Clinical failure or window into antipsychotic drug action?. Front. Neuroscience, 14.","DOI":"10.3389\/fnins.2020.600178"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1146\/annurev.biochem.76.060305.150444","article-title":"and J. Beavo, Biochemistry and Physiology of Cyclic Nucleotide Phosphodiesterases: Essential Components in Cyclic Nucleotide Signaling","volume":"76","author":"Conti","year":"2007","journal-title":"Annu. Rev. Biochem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/S0006-8993(03)02754-9","article-title":"Immunohistochemical localization of PDE10A in the rat brain","volume":"985","author":"Seeger","year":"2003","journal-title":"Brain Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1369\/jhc.6A6930.2006","article-title":"Immunohistochemical Localization of Phosphodiesterase 10A in Multiple Mammalian Species","volume":"54","author":"Coskran","year":"2006","journal-title":"J. Histochem. Cytochem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.neuropharm.2010.05.004","article-title":"Quantitative comparison of phosphodiesterase mRNA distribution in human brain and peripheral tissues","volume":"59","author":"Lakics","year":"2010","journal-title":"Neuropharmacology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1124\/jpet.107.132910","article-title":"Preclinical Characterization of Selective Phosphodiesterase 10A Inhibitors: A New Therapeutic Approach to the Treatment of Schizophrenia","volume":"325","author":"Schmidt","year":"2008","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1124\/jpet.108.146332","article-title":"Inhibition of Phosphodiesterase 10A Increases the Responsiveness of Striatal Projection Neurons to Cortical Stimulation","volume":"328","author":"Threlfell","year":"2009","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Polito, M., Guiot, E., Gangarossa, G., Longueville, S., Doulazmi, M., Valjent, E., Herve, D., Girault, J.A., Paupardin-Tritsch, D., and Castro, L.R. (2015). Selective Effects of PDE10A Inhibitors on Striatopallidal Neurons Require Phosphatase Inhibition by DARPP-32. eNeuro, 2.","DOI":"10.1523\/ENEURO.0060-15.2015"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1016\/j.neuropharm.2009.09.008","article-title":"Alterations in gene regulation following inhibition of the striatum-enriched phosphodiesterase, PDE10A","volume":"58","author":"Strick","year":"2010","journal-title":"Neuropharmacology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.neuropharm.2012.06.013","article-title":"The novel phosphodiesterase 10A inhibitor THPP-1 has antipsychotic-like effects in rat and improves cognition in rat and rhesus monkey","volume":"64","author":"Smith","year":"2013","journal-title":"Neuropharmacology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e00057","DOI":"10.1002\/prp2.57","article-title":"PDE10A inhibitors stimulate or suppress motor behavior dependent on the relative activation state of the direct and indirect striatal output pathways","volume":"2","author":"Megens","year":"2014","journal-title":"Pharmacol. Res. Perspect."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2252","DOI":"10.1038\/npp.2016.20","article-title":"TAK-063, a PDE10A inhibitor with balanced activation of direct and indirect pathways, provides potent antipsychotic-like effects in multiple paradigms","volume":"41","author":"Suzuki","year":"2016","journal-title":"Neuropsychopharmacology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"10460","DOI":"10.1523\/JNEUROSCI.2518-08.2008","article-title":"Distinct Roles of PDE4 and PDE10A in the Regulation of cAMP\/PKA Signaling in the Striatum","volume":"28","author":"Nishi","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.neuropharm.2013.10.015","article-title":"Phosphodiesterase 10A inhibitor MP-10 effects in primates: Comparison with risperidone and mechanistic implications","volume":"77","author":"Uthayathas","year":"2014","journal-title":"Neuropharmacology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1097\/JCP.0000000000001128","article-title":"Phosphodiesterase 10A Inhibitor Monotherapy Is Not an Effective Treatment of Acute Schizophrenia","volume":"39","author":"Walling","year":"2019","journal-title":"J. Clin. Psychopharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1097\/JCP.0000000000001047","article-title":"A Proof-of-Concept Study Evaluating the Phosphodiesterase 10A Inhibitor PF-02545920 in the Adjunctive Treatment of Suboptimally Controlled Symptoms of Schizophrenia","volume":"39","author":"DeMartinis","year":"2019","journal-title":"J. Clin. Psychopharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.schres.2018.08.028","article-title":"A phase 2, randomized, placebo-controlled study of the efficacy and safety of TAK-063 in subjects with an acute exacerbation of schizophrenia","volume":"204","author":"Macek","year":"2019","journal-title":"Schizophr. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1021\/acs.jmedchem.2c01521","article-title":"Discovery of MK-8189, a Highly Potent and Selective PDE10A Inhibitor for the Treatment of Schizophrenia","volume":"66","author":"Layton","year":"2023","journal-title":"J. Med. Chem."},{"key":"ref_45","first-page":"A99","article-title":"A randomized, double-blind, placebo-controlled phase ii efficacy and safety study of the PDE10A inhibitor PF-02545920 in Huntington Disease (AMARYLLIS)","volume":"89","author":"Delnomdedieu","year":"2018","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e00241","DOI":"10.1002\/prp2.241","article-title":"Pharmacological characterization of a novel potent, selective, and orally active phosphodiesterase 10A inhibitor, PDM-042 [(E)-4-(2-(2-(5,8-dimethyl-[1,2,4] triazolo [1,5-a] pyrazin-2-yl) vinyl)-6-(pyrrolidin-1-yl) pyrimidin-4-yl) morpholine] in rats: Potential for the treatment of schizophrenia","volume":"4","author":"Arakawa","year":"2016","journal-title":"Pharmacol. Res. Perspect."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1016\/S0149-7634(99)00037-8","article-title":"The conditioned avoidance response test re-evaluated: Is it a sensitive test for the detection of potentially atypical antipsychotics?","volume":"23","author":"Wadenberg","year":"1999","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1111\/j.2044-8341.1974.tb02285.x","article-title":"The use of analogue scales in rating subjective feelings","volume":"47","author":"Bond","year":"1974","journal-title":"Br. J. Med. Psychol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.schres.2005.02.013","article-title":"Manual for the extrapyramidal symptom rating scale (ESRS)","volume":"76","author":"Chouinard","year":"2005","journal-title":"Schizophr. Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1111\/j.1469-8986.1973.tb00801.x","article-title":"Quantification of sleepiness: A new approach","volume":"10","author":"Hoddes","year":"1973","journal-title":"Psychophysiology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1176\/appi.ajp.2011.10111704","article-title":"The Columbia\u2013Suicide Severity Rating Scale: Initial validity and internal consistency findings from three multisite studies with adolescents and adults","volume":"168","author":"Posner","year":"2011","journal-title":"Am. J. Psychiatry"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"595","DOI":"10.2967\/jnumed.113.131409","article-title":"Phosphodiesterase 10A PET radioligand development program: From pig to human","volume":"55","author":"Plisson","year":"2014","journal-title":"J. Nucl. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/S0893-133X(02)00304-4","article-title":"Dopamine D2 and D3 receptor occupancy in normal humans treated with the antipsychotic drug aripiprazole (OPC 14597): A study using positron emission tomography and [11C] raclopride","volume":"27","author":"Yokoi","year":"2002","journal-title":"Neuropsychopharmacology"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1007\/s002130050277","article-title":"The relationship between D2 receptor occupancy and plasma levels on low dose oral haloperidol: A PET study","volume":"131","author":"Kapur","year":"1997","journal-title":"Psychopharmacology"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"12352","DOI":"10.4088\/JCP.12m08189","article-title":"A multicenter, randomized, double-blind, placebo-controlled study of aripiprazole in children and adolescents with Tourette\u2019s disorder","volume":"74","author":"Yoo","year":"2013","journal-title":"J. Clin. Psychiatry"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"300","DOI":"10.2337\/db13-0247","article-title":"Genetic deletion and pharmacological inhibition of phosphodiesterase 10A protects mice from diet-induced obesity and insulin resistance","volume":"63","author":"Nawrocki","year":"2014","journal-title":"Diabetes"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.euroneuro.2022.05.009","article-title":"A double-blind, randomized, placebo-controlled proof of concept study of the efficacy and safety of Lu AF11167 for persistent negative symptoms in people with schizophrenia","volume":"61","author":"Nielsen","year":"2022","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.neuropharm.2017.01.016","article-title":"In vivo measurement of PDE10A enzyme occupancy by positron emission tomography (PET) following single oral dose administration of PF-02545920 in healthy male subjects","volume":"117","author":"Delnomdedieu","year":"2017","journal-title":"Neuropharmacology"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1093\/ijnp\/pyaa042","article-title":"Translational Development Strategies for TAK-063, a Phosphodiesterase 10A Inhibitor","volume":"23","author":"Macek","year":"2020","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1038\/s41593-023-01390-9","article-title":"Antipsychotic drug efficacy correlates with the modulation of D1 rather than D2 receptor-expressing striatal projection neurons","volume":"26","author":"Yun","year":"2023","journal-title":"Nat. Neurosci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.pharmthera.2018.06.012","article-title":"Molecular targets of atypical antipsychotics: From mechanism of action to clinical differences","volume":"192","author":"Aringhieri","year":"2018","journal-title":"Pharmacol. Ther."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/s10571-018-0632-3","article-title":"Dopamine: Functions, signaling, and association with neurological diseases","volume":"39","author":"Klein","year":"2019","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Giamp\u00e0, C., Laurenti, D., Anizilotti, S., Bernardi, G., Menniti, F.S., and Fusco, F.R. (PLoS ONE, 2010). Inhibition of the striatal specific phosphodiesterase PDE10A ameliorates striatal and cortical pathology in the R6\/2 mouse model of Huntington\u2019s disease, PLoS ONE, in press.","DOI":"10.1371\/journal.pone.0013417"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1124\/jpet.110.173294","article-title":"Chronic suppression of phosphodiesterase 10A alters striatal expression of genes responsible for neurotransmitter synthesis, neurotransmission, and signaling pathways implicated in Huntington\u2019s disease","volume":"336","author":"Kleiman","year":"2011","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"333","DOI":"10.3233\/JHD-190353","article-title":"A feasibility study of quantitative motor assessments in children using the Q-motor suite","volume":"8","author":"Schubert","year":"2019","journal-title":"J. Huntington\u2019s Dis."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.1001\/jamaneurol.2014.1954","article-title":"The phosphodiesterase 10 positron emission tomography tracer, [18F] MNI-659, as a novel biomarker for early Huntington disease","volume":"71","author":"Russell","year":"2014","journal-title":"JAMA Neurol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1212\/WNL.0000000000002391","article-title":"Change in PDE10 across early Huntington disease assessed by [18F] MNI-659 and PET imaging","volume":"86","author":"Russell","year":"2016","journal-title":"Neurology"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1111\/j.1460-9568.2008.06387.x","article-title":"Lowered cAMP and cGMP signalling in the brain during levodopa-induced dyskinesias in hemiparkinsonian rats: New aspects in the pathogenetic mechanisms","volume":"28","author":"Giorgi","year":"2008","journal-title":"Eur. J. Neurosci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.neuint.2014.10.004","article-title":"Levodopa-induced dyskinesias are associated with transient down- regulation of cAMP and cGMP in the caudate-putamen of hemiparkinsonian rats: Reduced synthesis or increased catabolism?","volume":"79","author":"Sancesario","year":"2014","journal-title":"Neurochem. Int."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1002\/mds.27341","article-title":"A selective phosphodiesterase 10A inhibitor reduces L-Dopa-induced dyskinesias in Parkinsonian monkeys","volume":"33","author":"Beck","year":"2018","journal-title":"Mov. Disord."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1097\/FBP.0000000000000084","article-title":"A new quantitative rating scale for dyskinesia in nonhuman primates","volume":"26","author":"Potts","year":"2015","journal-title":"Behav. Pharmacol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.jneumeth.2013.02.004","article-title":"Assessment of adverse effects of neurotropic drugs in monkeys with the \u201cdrug effects on the nervous system\u201d (DENS) scale","volume":"215","author":"Uthayathas","year":"2013","journal-title":"J. Neurosci. Methods"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.jfludis.2017.01.002","article-title":"Anomalous network architecture of the resting brain in children who stutter","volume":"55","author":"Chang","year":"2018","journal-title":"J. Fluen. Disord."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Qiao, J., Wang, Z., Zhao, G., Huo, Y., Herder, C.L., Sikora, C.O., and Peterson, B.S. (2017). Functional neural circuits that underlie developmental stuttering. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0179255"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Chang, S.-E., and Guenther, F.H. (2020). Involvement of the cortico-basal ganglia-thalamocortical loop in developmental stuttering. Front. Psychol., 10.","DOI":"10.3389\/fpsyg.2019.03088"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1097\/00004714-200008000-00013","article-title":"Risperidone for the treatment of stuttering","volume":"20","author":"Maguire","year":"2000","journal-title":"J. Clin. Psychopharmacol."},{"key":"ref_77","first-page":"S270","article-title":"Olanzapine versus haloperidol: Which can control stuttering better?","volume":"4","author":"Shaygannejad","year":"2013","journal-title":"Int. J. Prev. Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1016\/j.janxdis.2009.06.003","article-title":"Prevalence of anxiety disorders among adults seeking speech therapy for stuttering","volume":"23","author":"Iverach","year":"2009","journal-title":"J. Anxiety Disord."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Maguire, G.A., Nguyen, D.L., Simonson, K.C., and Kurz, T.L. (2020). The pharmacologic treatment of stuttering and its neuropharmacologic basis. Front. Neurosci., 14.","DOI":"10.3389\/fnins.2020.00158"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/14\/1230\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:20:50Z","timestamp":1760109650000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/14\/1230"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,22]]},"references-count":79,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2024,7]]}},"alternative-id":["cells13141230"],"URL":"https:\/\/doi.org\/10.3390\/cells13141230","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,22]]}}}