{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T02:26:46Z","timestamp":1790735206078,"version":"4.1.0"},"reference-count":64,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,12,16]],"date-time":"2021-12-16T00:00:00Z","timestamp":1639612800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"publisher","award":["MH121454"],"award-info":[{"award-number":["MH121454"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the Research and Education Initiative Fund, a component of the Advancing a Healthier Wisconsin endowment at the Medical College of Wisconsin","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Parkinson\u2019s disease (PD) is a chronic neurodegenerative disorder associated with dopamine neuron loss and motor dysfunction. Neuroprotective agents that prevent dopamine neuron death hold great promise for slowing the disease\u2019s progression. The activation of cannabinoid (CB) receptors has shown neuroprotective effects in preclinical models of neurodegenerative disease, traumatic brain injury, and stroke, and may provide neuroprotection against PD. Here, we report that the selective CB2 agonist GW842166x exerted protective effects against the 6-hydroxydopamine (6-OHDA)-induced loss of dopamine neurons and its associated motor function deficits in mice, as shown by an improvement in balance beam walking, pole, grip strength, rotarod, and amphetamine-induced rotation tests. The neuroprotective effects of GW842166x were prevented by the CB2 receptor antagonist AM630, suggesting a CB2-dependent mechanism. To investigate potential mechanisms for the neuroprotective effects of GW842166x, we performed electrophysiological recordings from substantia nigra pars compacta (SNc) dopamine neurons in ex vivo midbrain slices prepared from drug-na\u00efve mice. We found that the bath application of GW842166x led to a decrease in action potential firing, likely due to a decrease in hyperpolarization-activated currents (Ih) and a shift of the half-activation potential (V1\/2) of Ih to a more hyperpolarized level. Taken together, the CB2 agonist GW842166x may reduce the vulnerability of dopamine neurons to 6-OHDA by decreasing the action potential firing of these neurons and the associated calcium load.<\/jats:p>","DOI":"10.3390\/cells10123548","type":"journal-article","created":{"date-parts":[[2021,12,16]],"date-time":"2021-12-16T11:27:36Z","timestamp":1639654056000},"page":"3548","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["The Neuroprotective Effects of the CB2 Agonist GW842166x in the 6-OHDA Mouse Model of Parkinson\u2019s Disease"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2346-4268","authenticated-orcid":false,"given":"Hao","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA"},{"name":"Department of Exercise Physiology, Beijing Sport University, Beijing 100084, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9843-1674","authenticated-orcid":false,"given":"Xiaojie","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bixuan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0536-1211","authenticated-orcid":false,"given":"Casey R.","family":"Vickstrom","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5567-2520","authenticated-orcid":false,"given":"Vladislav","family":"Friedman","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas J.","family":"Kelly","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9342-4480","authenticated-orcid":false,"given":"Xiaowen","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Exercise Physiology, Beijing Sport University, Beijing 100084, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9678-748X","authenticated-orcid":false,"given":"Cecilia J.","family":"Hillard","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1858-1504","authenticated-orcid":false,"given":"Qing-Song","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/j.neuron.2016.03.038","article-title":"Understanding dopaminergic cell death pathways in Parkinson disease","volume":"90","author":"Michel","year":"2016","journal-title":"Neuron"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.lfs.2019.03.057","article-title":"Parkinson\u2019s disease: Mechanisms, translational models and management strategies","volume":"226","author":"Raza","year":"2019","journal-title":"Life Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"a009282","DOI":"10.1101\/cshperspect.a009282","article-title":"Motor control abnormalities in Parkinson\u2019s disease","volume":"2","author":"Mazzoni","year":"2012","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_4","first-page":"Doc05","article-title":"The treatment of Parkinson\u2019s disease with dopamine agonists","volume":"4","author":"Konta","year":"2008","journal-title":"GMS Health Technol. Assess."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1056\/NEJMoa033447","article-title":"Levodopa and the progression of Parkinson\u2019s disease","volume":"351","author":"Fahn","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/S1474-4422(17)30004-2","article-title":"Impulse control disorders and levodopa-induced dyskinesias in Parkinson\u2019s disease: An update","volume":"16","author":"Voon","year":"2017","journal-title":"Lancet Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1111\/jnc.14098","article-title":"Endocannabinoid system in neurodegenerative disorders","volume":"142","author":"Basavarajappa","year":"2017","journal-title":"J. Neurochem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1016\/j.celrep.2012.09.030","article-title":"Monoacylglycerol lipase is a therapeutic target for Alzheimer\u2019s disease","volume":"2","author":"Chen","year":"2012","journal-title":"Cell Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1126\/science.1209200","article-title":"Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation","volume":"334","author":"Nomura","year":"2011","journal-title":"Science"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6508","DOI":"10.4049\/jimmunol.1102435","article-title":"Cannabinoid receptor type 1 protects nigrostriatal dopaminergic neurons against MPTP neurotoxicity by inhibiting microglial activation","volume":"187","author":"Chung","year":"2011","journal-title":"J. Immunol."},{"key":"ref_11","first-page":"2173","article-title":"The CB1 cannabinoid receptor agonist reduces L-DOPA-induced motor fluctuation and ERK1\/2 phosphorylation in 6-OHDA-lesioned rats","volume":"8","author":"Song","year":"2014","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.brainres.2010.09.086","article-title":"The effects of cannabinoid drugs on abnormal involuntary movements in dyskinetic and non-dyskinetic 6-hydroxydopamine lesioned rats","volume":"1363","author":"Walsh","year":"2010","journal-title":"Brain Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.brainres.2012.02.058","article-title":"Cannabinoids prevent lipopolysaccharide-induced neurodegeneration in the rat substantia nigra in vivo through inhibition of microglial activation and NADPH oxidase","volume":"1451","author":"Chung","year":"2012","journal-title":"Brain Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2177","DOI":"10.1111\/j.1460-9568.2009.06764.x","article-title":"WIN55,212-2, a cannabinoid receptor agonist, protects against nigrostriatal cell loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson\u2019s disease","volume":"29","author":"Price","year":"2009","journal-title":"Eur. J. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2108","DOI":"10.1212\/WNL.57.11.2108","article-title":"Cannabinoids reduce levodopa-induced dyskinesia in Parkinson\u2019s disease: A pilot study","volume":"57","author":"Sieradzan","year":"2001","journal-title":"Neurology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1002\/mds.10289","article-title":"Stimulation of cannabinoid receptors reduces levodopa-induced dyskinesia in the MPTP-lesioned nonhuman primate model of Parkinson\u2019s disease","volume":"17","author":"Fox","year":"2002","journal-title":"Mov. Disord. Off. J. Mov. Disord. Soc."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1002\/mds.1280","article-title":"Randomised, double-blind, placebo-controlled trial to assess the potential of cannabinoid receptor stimulation in the treatment of dystonia","volume":"17","author":"Fox","year":"2002","journal-title":"Mov. Disord. Off. J. Mov. Disord. Soc."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1124\/mol.114.094649","article-title":"CB2 Cannabinoid receptors as a therapeutic target-what does the future hold?","volume":"86","author":"Dhopeshwarkar","year":"2014","journal-title":"Mol. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"E5007","DOI":"10.1073\/pnas.1413210111","article-title":"Cannabinoid CB2 receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice","volume":"111","author":"Zhang","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neulet.2014.12.003","article-title":"Identification of CB(2) receptors in human nigral neurons that degenerate in Parkinson\u2019s disease","volume":"587","author":"Garcia","year":"2015","journal-title":"Neurosci. Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1111\/adb.12367","article-title":"Expression of functional cannabinoid CB2 receptor in VTA dopamine neurons in rats","volume":"22","author":"Zhang","year":"2017","journal-title":"Addict. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1007\/s13311-018-0603-x","article-title":"Cannabinoid CB1 and CB2 receptors, and monoacylglycerol lipase gene expression alterations in the basal ganglia of patients with Parkinson\u2019s disease","volume":"15","author":"Navarrete","year":"2018","journal-title":"Neurotherapeutics"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"321","DOI":"10.3389\/fnins.2016.00321","article-title":"Cannabinoid type 2 (CB2) receptors activation protects against oxidative stress and neuroinflammation associated dopaminergic neurodegeneration in rotenone model of Parkinson\u2019s disease","volume":"10","author":"Javed","year":"2016","journal-title":"Front. Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.tips.2006.11.001","article-title":"Cannabinoid CB2 receptor: A new target for controlling neural cell survival?","volume":"28","author":"Romero","year":"2007","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/0006-8993(70)90187-3","article-title":"Quantitative recording of rotational behavior in rats after 6-hydroxy-dopamine lesions of the nigrostriatal dopamine system","volume":"24","author":"Ungerstedt","year":"1970","journal-title":"Brain Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/0028-3908(73)90061-0","article-title":"Turning behavior of mice with unilateral 6-hydroxydopamine lesions in the striatum: Effects of apomorphine, L-DOPA, amanthadine, amphetamine and other psychomotor stimulants","volume":"12","author":"Moore","year":"1973","journal-title":"Neuropharmacology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1097\/AJP.0b013e318219799a","article-title":"A randomized, controlled study to investigate the analgesic efficacy of single doses of the cannabinoid receptor-2 agonist GW842166, ibuprofen or placebo in patients with acute pain following third molar tooth extraction","volume":"27","author":"Ostenfeld","year":"2011","journal-title":"Clin. J. Pain"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.neuron.2009.01.033","article-title":"Interplay between cytosolic dopamine, calcium, and alpha-synuclein causes selective death of substantia nigra neurons","volume":"62","author":"Mosharov","year":"2009","journal-title":"Neuron"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1038\/nature05865","article-title":"\u2019Rejuvenation\u2019 protects neurons in mouse models of Parkinson\u2019s disease","volume":"447","author":"Chan","year":"2007","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"10736","DOI":"10.1074\/jbc.R112.410530","article-title":"Calcium, bioenergetics, and neuronal vulnerability in Parkinson\u2019s disease","volume":"288","author":"Surmeier","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1111\/jnc.13572","article-title":"Converging roles of ion channels, calcium, metabolic stress, and activity pattern of Substantia nigra dopaminergic neurons in health and Parkinson\u2019s disease","volume":"139","author":"Duda","year":"2016","journal-title":"J. Neurochem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"11011","DOI":"10.1523\/JNEUROSCI.2519-09.2009","article-title":"Robust pacemaking in substantia nigra dopaminergic neurons","volume":"29","author":"Guzman","year":"2009","journal-title":"J Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2266","DOI":"10.1172\/JCI95898","article-title":"Systemic isradipine treatment diminishes calcium-dependent mitochondrial oxidant stress","volume":"128","author":"Guzman","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.ebiom.2019.03.040","article-title":"Mechanisms of cannabinoid CB2 receptor-mediated reduction of dopamine neuronal excitability in mouse ventral tegmental area","volume":"42","author":"Ma","year":"2019","journal-title":"EBioMedicine"},{"key":"ref_35","first-page":"290","article-title":"A mouse model of non-motor symptoms in Parkinson\u2019s disease: Focus on pharmacological interventions targeting affective dysfunctions","volume":"8","author":"Masini","year":"2014","journal-title":"Front. Behav. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e32420","DOI":"10.7554\/eLife.32420","article-title":"HCN2 channels in the ventral tegmental area regulate behavioral responses to chronic stress","volume":"7","author":"Zhong","year":"2018","journal-title":"eLife"},{"key":"ref_37","first-page":"53825","article-title":"Preparation of acute brain slices using an optimized N-Methyl-D-Glucamine protective recovery method","volume":"132","author":"Ting","year":"2018","journal-title":"J. Vis. Exp."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/S0165-0270(96)02211-X","article-title":"Pole test is a useful method for evaluating the mouse movement disorder caused by striatal dopamine depletion","volume":"73","author":"Matsuura","year":"1997","journal-title":"J. Neurosci. Methods"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e2237","DOI":"10.21769\/BioProtoc.2237","article-title":"Evaluation of muscle performance in mice by treadmill exhaustion test and whole-limb grip strength assay","volume":"7","author":"Castro","year":"2017","journal-title":"Bio. Protoc."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1152\/physiolgenomics.90207.2008","article-title":"Reliability, robustness, and reproducibility in mouse behavioral phenotyping: A cross-laboratory study","volume":"34","author":"Mandillo","year":"2008","journal-title":"Physiol. Genom."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"17","DOI":"10.3233\/JPD-181525","article-title":"The amphetamine induced rotation test: A re-assessment of its use as a tool to monitor motor impairment and functional recovery in rodent models of Parkinson\u2019s disease","volume":"9","author":"Dunnett","year":"2019","journal-title":"J. Parkinson\u2019s Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1007\/s11064-010-0133-3","article-title":"Molecular profiling of a 6-hydroxydopamine model of Parkinson\u2019s disease","volume":"35","author":"Na","year":"2010","journal-title":"Neurochem. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2597","DOI":"10.1021\/jm061195+","article-title":"Discovery of 2-[(2,4-dichlorophenyl)amino]-N-[(tetrahydro- 2H-pyran-4-yl)methyl]-4-(trifluoromethyl)- 5-pyrimidinecarboxamide, a selective CB2 receptor agonist for the treatment of inflammatory pain","volume":"50","author":"Giblin","year":"2007","journal-title":"J. Med. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1038\/sj.bjp.0702351","article-title":"Agonist-inverse agonist characterization at CB1 and CB2 cannabinoid receptors of L759633, L759656, and AM630","volume":"126","author":"Ross","year":"1999","journal-title":"Br. J. Pharmacol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/nrn.2016.178","article-title":"Selective neuronal vulnerability in Parkinson disease","volume":"18","author":"Surmeier","year":"2017","journal-title":"Nat. Rev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"7234","DOI":"10.1523\/JNEUROSCI.0459-16.2016","article-title":"Differential somatic Ca2+ channel profile in midbrain dopaminergic neurons","volume":"36","author":"Philippart","year":"2016","journal-title":"J. Neurosci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1111\/j.1749-6632.1992.tb24523.x","article-title":"Midbrain dopaminergic cell loss in Parkinson\u2019s disease and MPTP-induced parkinsonism: Sparing of calbindin-D28k-containing cells","volume":"648","author":"German","year":"1992","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1056\/NEJM198804073181402","article-title":"Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson\u2019s disease. Pathophysiologic and clinical implications","volume":"318","author":"Kish","year":"1988","journal-title":"N. Engl. J. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1089\/can.2016.0037","article-title":"Cannabinoid CB1 and CB2 receptor signaling and bias","volume":"2","author":"Ibsen","year":"2017","journal-title":"Cannabis Cannabinoid Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1002\/acn3.412","article-title":"A novel design of a Phase III trial of isradipine in early Parkinson disease (STEADY-PD III)","volume":"4","author":"Biglan","year":"2017","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/978-3-540-68964-5_7","article-title":"Cyclic nucleotide-gated channels","volume":"191","author":"Biel","year":"2009","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1038\/35081088","article-title":"Molecular mechanism of cAMP modulation of HCN pacemaker channels","volume":"411","author":"Wainger","year":"2001","journal-title":"Nature"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2685","DOI":"10.1046\/j.1460-9568.2000.00151.x","article-title":"Single-cell mRNA expression of HCN1 correlates with a fast gating phenotype of hyperpolarization-activated cyclic nucleotide-gated ion channels (Ih) in central neurons","volume":"12","author":"Franz","year":"2000","journal-title":"Eur. J. Neurosci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"5264","DOI":"10.1523\/JNEUROSCI.20-14-05264.2000","article-title":"Molecular and functional heterogeneity of hyperpolarization-activated pacemaker channels in the mouse CNS","volume":"20","author":"Santoro","year":"2000","journal-title":"J. Neurosci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1085\/jgp.118.3.237","article-title":"Regulation of hyperpolarization-activated HCN channel gating and cAMP modulation due to interactions of COOH terminus and core transmembrane regions","volume":"118","author":"Wang","year":"2001","journal-title":"J. Gen. Physiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"S183","DOI":"10.1016\/S1353-8020(11)70057-8","article-title":"Animal models of Parkinson\u2019s disease","volume":"18","author":"Blesa","year":"2012","journal-title":"Park. Relat. Disord."},{"key":"ref_57","unstructured":"Stoker, T.B., and Greenland, J.C. (2018). Animal models of Parkinson\u2019s disease. Parkinson\u2019s Disease: Pathogenesis and Clinical Aspects, Codon Publications."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"67837","DOI":"10.18632\/oncotarget.18871","article-title":"AM1241 alleviates MPTP-induced Parkinson\u2019s disease and promotes the regeneration of DA neurons in PD mice","volume":"8","author":"Shi","year":"2017","journal-title":"Oncotarget"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.1111\/j.1476-5381.2011.01278.x","article-title":"Symptom-relieving and neuroprotective effects of the phytocannabinoid \u0394(9)-THCV in animal models of Parkinson\u2019s disease","volume":"163","author":"Ramos","year":"2011","journal-title":"Br. J. Pharmacol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.bbr.2011.11.027","article-title":"Unilateral nigrostriatal 6-hydroxydopamine lesions in mice I: Motor impairments identify extent of dopamine depletion at three different lesion sites","volume":"228","author":"Heuer","year":"2012","journal-title":"Behav. Brain Res."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Gambardella, C., Pignatelli, A., and Belluzzi, O. (2012). The h-current in the substantia Nigra pars compacta neurons: A re-examination. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0052329"},{"key":"ref_62","first-page":"533","article-title":"The 6-hydroxydopamine model and parkinsonian pathophysiology: Novel findings in an older model","volume":"32","year":"2017","journal-title":"Neurologia"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.expneurol.2015.04.007","article-title":"Differential upregulation of the cannabinoid CB(2) receptor in neurotoxic and inflammation-driven rat models of Parkinson\u2019s disease","volume":"269","author":"Concannon","year":"2015","journal-title":"Exp. Neurol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"109745","DOI":"10.1016\/j.pnpbp.2019.109745","article-title":"The therapeutic role of cannabinoid receptors and its agonists or antagonists in Parkinson\u2019s disease","volume":"96","author":"Han","year":"2020","journal-title":"Prog. Neuro Psychopharmacol. Biol. Psychiatry"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/12\/3548\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:49:12Z","timestamp":1760168952000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/12\/3548"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,16]]},"references-count":64,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["cells10123548"],"URL":"https:\/\/doi.org\/10.3390\/cells10123548","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,16]]}}}