{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,11]],"date-time":"2026-11-11T15:45:55Z","timestamp":1794411955416,"version":"4.9.0"},"reference-count":62,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T00:00:00Z","timestamp":1746576000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T00:00:00Z","timestamp":1746576000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MC_UU_12024\/2"],"award-info":[{"award-number":["MC_UU_12024\/2"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013373","name":"NIHR Oxford Biomedical Research Centre","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013373","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>We conducted PET imaging with [<jats:sup>18<\/jats:sup>F]FDOPA and dopamine D2\/3 receptor ligand [<jats:sup>18<\/jats:sup>F]fallypride in aged transgenic rats carrying human pathogenic <jats:italic>LRRK2<\/jats:italic> R1441C or G2019S mutations. These rats have mild age-dependent deficits in dopamine release restricted to dorsal striatum despite no overt loss of dopamine neurons or dopamine content and demonstrate L-DOPA-responsive movement deficits.<\/jats:p>\n          <jats:p>\n            <jats:italic>LRRK2<\/jats:italic> mutant rats displayed no deficit in [<jats:sup>18<\/jats:sup>F]FDOPA uptake, consistent with intact dopamine synthesis in striatal axons. However, <jats:italic>LRRK2<\/jats:italic>-R1441C rats demonstrated greater binding of [<jats:sup>18<\/jats:sup>F]fallypride than <jats:italic>LRRK2<\/jats:italic>-G2019S or non-transgenic controls, from a regionally selective increase in dorsal striatum. Immunocytochemical labelling post-mortem confirmed a greater density of D2 receptors in <jats:italic>LRRK2<\/jats:italic>-R1441C than other genotypes restricted to dorsal striatum, consistent with upregulation of D2-receptors as a compensatory response to the greater dopamine release deficit previously demonstrated in this genotype.<\/jats:p>\n          <jats:p>These results show that [<jats:sup>18<\/jats:sup>F]fallypride PET imaging is sensitive to dysregulation of dopamine signalling in the <jats:italic>LRRK2<\/jats:italic>-R1441C rat, revealing upregulation of D2 receptors that parallels observations in human putamen in early sporadic PD. Future studies of candidate therapies could exploit this non-invasive approach to assess treatment efficacy.<\/jats:p>","DOI":"10.1038\/s41598-025-99580-x","type":"journal-article","created":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T12:39:50Z","timestamp":1746621590000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Dopamine D2 receptor upregulation in dorsal striatum in the LRRK2-R1441C rat model of early Parkinson\u2019s disease revealed by in vivo PET imaging"],"prefix":"10.1038","volume":"15","author":[{"given":"Teresa","family":"Delgado-Go\u00f1i","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Connor-Robson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milena","family":"Cioroch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Paisey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Marshall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma L.","family":"Lane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Hauton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"McCullagh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Magill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie J.","family":"Cragg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clare E.","family":"Mackay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Wade-Martins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes C.","family":"Klein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,7]]},"reference":[{"key":"99580_CR1","doi-asserted-by":"publisher","first-page":"17013","DOI":"10.1038\/nrdp.2017.13","volume":"3","author":"W Poewe","year":"2017","unstructured":"Poewe, W. et al. Parkinson disease. Nat. Rev. Dis. Primers 3, 17013. https:\/\/doi.org\/10.1038\/nrdp.2017.13 (2017).","journal-title":"Nat. Rev. Dis. Primers"},{"key":"99580_CR2","doi-asserted-by":"publisher","first-page":"708","DOI":"10.1038\/nrneurol.2014.205","volume":"10","author":"M Politis","year":"2014","unstructured":"Politis, M. Neuroimaging in Parkinson disease: From research setting to clinical practice. Nat. Rev. Neurol. 10, 708\u2013722. https:\/\/doi.org\/10.1038\/nrneurol.2014.205 (2014).","journal-title":"Nat. Rev. Neurol."},{"key":"99580_CR3","doi-asserted-by":"publisher","first-page":"1042","DOI":"10.1016\/j.neuron.2019.03.004","volume":"101","author":"MM McGregor","year":"2019","unstructured":"McGregor, M. M. & Nelson, A. B. Circuit mechanisms of Parkinson\u2019s disease. Neuron 101, 1042\u20131056. https:\/\/doi.org\/10.1016\/j.neuron.2019.03.004 (2019).","journal-title":"Neuron"},{"key":"99580_CR4","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1016\/s0896-6273(03)00568-3","volume":"39","author":"W Dauer","year":"2003","unstructured":"Dauer, W. & Przedborski, S. Parkinson\u2019s disease: Mechanisms and models. Neuron 39, 889\u2013909. https:\/\/doi.org\/10.1016\/s0896-6273(03)00568-3 (2003).","journal-title":"Neuron"},{"key":"99580_CR5","doi-asserted-by":"publisher","first-page":"2419","DOI":"10.1093\/brain\/awt192","volume":"136","author":"JH Kordower","year":"2013","unstructured":"Kordower, J. H. et al. Disease duration and the integrity of the nigrostriatal system in Parkinson\u2019s disease. Brain 136, 2419\u20132431. https:\/\/doi.org\/10.1093\/brain\/awt192 (2013).","journal-title":"Brain"},{"key":"99580_CR6","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1007\/s00702-017-1686-y","volume":"124","author":"OB Tysnes","year":"2017","unstructured":"Tysnes, O. B. & Storstein, A. Epidemiology of Parkinson\u2019s disease. J. Neural Transm. (Vienna) 124, 901\u2013905. https:\/\/doi.org\/10.1007\/s00702-017-1686-y (2017).","journal-title":"J. Neural Transm. (Vienna)"},{"key":"99580_CR7","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/j.bbr.2017.10.021","volume":"352","author":"S Vingill","year":"2018","unstructured":"Vingill, S., Connor-Robson, N. & Wade-Martins, R. Are rodent models of Parkinson\u2019s disease behaving as they should?. Behav. Brain Res. 352, 133\u2013141. https:\/\/doi.org\/10.1016\/j.bbr.2017.10.021 (2018).","journal-title":"Behav. Brain Res."},{"key":"99580_CR8","doi-asserted-by":"publisher","first-page":"E4016","DOI":"10.1073\/pnas.1309143110","volume":"110","author":"S Janezic","year":"2013","unstructured":"Janezic, S. et al. Deficits in dopaminergic transmission precede neuron loss and dysfunction in a new Parkinson model. Proc. Natl. Acad. Sci. U S A 110, E4016-4025. https:\/\/doi.org\/10.1073\/pnas.1309143110 (2013).","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"99580_CR9","doi-asserted-by":"publisher","first-page":"16615","DOI":"10.1038\/srep16615","volume":"5","author":"N Ninkina","year":"2015","unstructured":"Ninkina, N. et al. A novel resource for studying function and dysfunction of alpha-synuclein: Mouse lines for modulation of endogenous Snca gene expression. Sci. Rep. 5, 16615. https:\/\/doi.org\/10.1038\/srep16615 (2015).","journal-title":"Sci. Rep."},{"key":"99580_CR10","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1093\/hmg\/ddv628","volume":"25","author":"M Sloan","year":"2016","unstructured":"Sloan, M. et al. LRRK2 BAC transgenic rats develop progressive, L-DOPA-responsive motor impairment, and deficits in dopamine circuit function. Hum. Mol. Genet. 25, 951\u2013963. https:\/\/doi.org\/10.1093\/hmg\/ddv628 (2016).","journal-title":"Hum. Mol. Genet."},{"key":"99580_CR11","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1016\/j.nbd.2015.02.031","volume":"78","author":"M Yue","year":"2015","unstructured":"Yue, M. et al. Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S knock-in mice. Neurobiol. Dis. 78, 172\u2013195. https:\/\/doi.org\/10.1016\/j.nbd.2015.02.031 (2015).","journal-title":"Neurobiol. Dis."},{"issue":"Suppl 1","key":"99580_CR12","doi-asserted-by":"publisher","first-page":"S35","DOI":"10.1016\/S1353-8020(13)70011-7","volume":"20","author":"M Spatola","year":"2014","unstructured":"Spatola, M. & Wider, C. Genetics of Parkinson\u2019s disease: The yield. Parkinsonism Relat. Disord. 20(Suppl 1), S35-38. https:\/\/doi.org\/10.1016\/S1353-8020(13)70011-7 (2014).","journal-title":"Parkinsonism Relat. Disord."},{"key":"99580_CR13","doi-asserted-by":"publisher","first-page":"1759","DOI":"10.1002\/mds.26281","volume":"30","author":"F Baig","year":"2015","unstructured":"Baig, F. et al. Delineating nonmotor symptoms in early Parkinson\u2019s disease and first-degree relatives. Mov. Disord. 30, 1759\u20131766. https:\/\/doi.org\/10.1002\/mds.26281 (2015).","journal-title":"Mov. Disord."},{"key":"99580_CR14","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1186\/1750-1326-9-47","volume":"9","author":"JQ Li","year":"2014","unstructured":"Li, J. Q., Tan, L. & Yu, J. T. The role of the LRRK2 gene in Parkinsonism. Mol. Neurodegener. 9, 47. https:\/\/doi.org\/10.1186\/1750-1326-9-47 (2014).","journal-title":"Mol. Neurodegener."},{"key":"99580_CR15","doi-asserted-by":"publisher","first-page":"1733","DOI":"10.1002\/mds.23735","volume":"26","author":"C Criscuolo","year":"2011","unstructured":"Criscuolo, C. et al. The LRRK2 R1441C mutation is more frequent than G2019S in Parkinson\u2019s disease patients from southern Italy. Mov. Disord. 26, 1733\u20131736. https:\/\/doi.org\/10.1002\/mds.23735 (2011).","journal-title":"Mov. Disord."},{"key":"99580_CR16","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1111\/ejn.14300","volume":"49","author":"LS Breger","year":"2019","unstructured":"Breger, L. S. & Fuzzati Armentero, M. T. Genetically engineered animal models of Parkinson\u2019s disease: From worm to rodent. Eur. J. Neurosci. 49, 533\u2013560. https:\/\/doi.org\/10.1111\/ejn.14300 (2019).","journal-title":"Eur. J. Neurosci."},{"key":"99580_CR17","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1002\/mds.27296","volume":"33","author":"RB Creed","year":"2018","unstructured":"Creed, R. B. & Goldberg, M. S. New developments in genetic rat models of Parkinson\u2019s disease. Mov. Disord. 33, 717\u2013729. https:\/\/doi.org\/10.1002\/mds.27296 (2018).","journal-title":"Mov. Disord."},{"key":"99580_CR18","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1042\/BST20160238","volume":"45","author":"M Volta","year":"2017","unstructured":"Volta, M. & Melrose, H. LRRK2 mouse models: dissecting the behavior, striatal neurochemistry and neurophysiology of PD pathogenesis. Biochem. Soc. Trans. 45, 113\u2013122. https:\/\/doi.org\/10.1042\/BST20160238 (2017).","journal-title":"Biochem. Soc. Trans."},{"key":"99580_CR19","doi-asserted-by":"publisher","first-page":"1635","DOI":"10.1073\/pnas.1712648115","volume":"115","author":"Y Xiong","year":"2018","unstructured":"Xiong, Y. et al. Robust kinase- and age-dependent dopaminergic and norepinephrine neurodegeneration in LRRK2 G2019S transgenic mice. Proc. Natl. Acad. Sci. U S A 115, 1635\u20131640. https:\/\/doi.org\/10.1073\/pnas.1712648115 (2018).","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"99580_CR20","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1016\/j.nbd.2019.04.005","volume":"127","author":"N Connor-Robson","year":"2019","unstructured":"Connor-Robson, N. et al. An integrated transcriptomics and proteomics analysis reveals functional endocytic dysregulation caused by mutations in LRRK2. Neurobiol. Dis. 127, 512\u2013526. https:\/\/doi.org\/10.1016\/j.nbd.2019.04.005 (2019).","journal-title":"Neurobiol. Dis."},{"key":"99580_CR21","doi-asserted-by":"publisher","first-page":"2696","DOI":"10.1093\/hmg\/ddz088","volume":"28","author":"R Wallings","year":"2019","unstructured":"Wallings, R., Connor-Robson, N. & Wade-Martins, R. LRRK2 interacts with the vacuolar-type H+-ATPase pump a1 subunit to regulate lysosomal function. Hum. Mol. Genet. 28, 2696\u20132710. https:\/\/doi.org\/10.1093\/hmg\/ddz088 (2019).","journal-title":"Hum. Mol. Genet."},{"issue":"1","key":"99580_CR22","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.bbr.2009.06.008","volume":"204","author":"S Nikolaus","year":"2009","unstructured":"Nikolaus, S., Antke, C. & M\u00fcller, H. W. In vivo imaging of synaptic function in the central nervous system. Behav. Brain Res. 204(1), 1\u201331. https:\/\/doi.org\/10.1016\/j.bbr.2009.06.008 (2009).","journal-title":"Behav. Brain Res."},{"issue":"04","key":"99580_CR23","doi-asserted-by":"publisher","first-page":"155","DOI":"10.3413\/Nukmed-0371-10-12","volume":"50","author":"S Nikolaus","year":"2011","unstructured":"Nikolaus, S. et al. In vivo imaging neurotransmitter function: The rat 6-hydroxydopamine model and its relevance for human Parkinson\u2019s disease. Nuklearmedizin 50(04), 155\u2013156. https:\/\/doi.org\/10.3413\/Nukmed-0371-10-12 (2011).","journal-title":"Nuklearmedizin"},{"key":"99580_CR24","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1016\/j.neuron.2010.04.034","volume":"66","author":"TM Dawson","year":"2010","unstructured":"Dawson, T. M., Ko, H. S. & Dawson, V. L. Genetic animal models of Parkinson\u2019s disease. Neuron 66, 646\u2013661. https:\/\/doi.org\/10.1016\/j.neuron.2010.04.034 (2010).","journal-title":"Neuron"},{"key":"99580_CR25","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1007\/s11307-007-0093-4","volume":"9","author":"EM Strome","year":"2007","unstructured":"Strome, E. M. & Doudet, D. J. Animal models of neurodegenerative disease: insights from in vivo imaging studies. Mol. Imaging Biol. 9, 186\u2013195. https:\/\/doi.org\/10.1007\/s11307-007-0093-4 (2007).","journal-title":"Mol. Imaging Biol."},{"key":"99580_CR26","first-page":"65","volume":"41","author":"V Kaasinen","year":"2000","unstructured":"Kaasinen, V. et al. Upregulation of putaminal dopamine D2 receptors in early Parkinson\u2019s disease: A comparative PET study with [11C] raclopride and [11C]N-methylspiperone. J. Nucl. Med. 41, 65\u201370 (2000).","journal-title":"J. Nucl. Med."},{"key":"99580_CR27","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1016\/0022-510x(95)00137-q","volume":"132","author":"JO Rinne","year":"1995","unstructured":"Rinne, J. O. et al. Increased density of dopamine D2 receptors in the putamen, but not in the caudate nucleus in early Parkinson\u2019s disease: A PET study with [11C]raclopride. J. Neurol. Sci. 132, 156\u2013161. https:\/\/doi.org\/10.1016\/0022-510x(95)00137-q (1995).","journal-title":"J. Neurol. Sci."},{"key":"99580_CR28","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1126\/science.877576","volume":"197","author":"I Creese","year":"1977","unstructured":"Creese, I., Burt, D. R. & Snyder, S. H. Dopamine receptor binding enhancement accompanies lesion-induced behavioral supersensitivity. Science 197, 596\u2013598. https:\/\/doi.org\/10.1126\/science.877576 (1977).","journal-title":"Science"},{"issue":"3","key":"99580_CR29","doi-asserted-by":"publisher","first-page":"587","DOI":"10.3390\/molecules23030587","volume":"23","author":"T Mann","year":"2018","unstructured":"Mann, T. et al. [18F]fallypride-PET\/CT analysis of the dopamine D2\/D3 receptor in the hemiparkinsonian rat brain following intrastriatal botulinum neurotoxin a injection. Molecules 23(3), 587. https:\/\/doi.org\/10.3390\/molecules23030587 (2018).","journal-title":"Molecules"},{"key":"99580_CR30","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/0006-8993(88)91074-8","volume":"445","author":"KL Leenders","year":"1988","unstructured":"Leenders, K. L. et al. Unilateral MPTP lesion in a rhesus monkey: effects on the striatal dopaminergic system measured in vivo with PET using various novel tracers. Brain Res. 445, 61\u201367. https:\/\/doi.org\/10.1016\/0006-8993(88)91074-8 (1988).","journal-title":"Brain Res."},{"issue":"3","key":"99580_CR31","doi-asserted-by":"publisher","first-page":"483","DOI":"10.3233\/JPD-140344","volume":"4","author":"MD Walker","year":"2014","unstructured":"Walker, M. D. et al. Behavioral deficits and striatal DA signaling in LRRK2 p.G2019S transgenic rats: a multimodal investigation including PET neuroimaging. J. Parkinson\u2019s Disease 4(3), 483\u2013498. https:\/\/doi.org\/10.3233\/JPD-140344 (2014).","journal-title":"J. Parkinson\u2019s Disease"},{"key":"99580_CR32","first-page":"323","volume":"3","author":"C Loane","year":"2011","unstructured":"Loane, C. & Politis, M. Positron emission tomography neuroimaging in Parkinson\u2019s disease. Am. J. Transl. Res. 3, 323\u2013341 (2011).","journal-title":"Am. J. Transl. Res."},{"key":"99580_CR33","doi-asserted-by":"publisher","first-page":"2777","DOI":"10.1002\/mds.23407","volume":"25","author":"MG Vuckovic","year":"2010","unstructured":"Vuckovic, M. G. et al. Exercise elevates dopamine D2 receptor in a mouse model of Parkinson\u2019s disease: In vivo imaging with [(1)(8)F]fallypride. Mov. Disord. 25, 2777\u20132784. https:\/\/doi.org\/10.1002\/mds.23407 (2010).","journal-title":"Mov. Disord."},{"key":"99580_CR34","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.brainres.2007.04.043","volume":"1156","author":"KY Araki","year":"2007","unstructured":"Araki, K. Y., Sims, J. R. & Bhide, P. G. Dopamine receptor mRNA and protein expression in the mouse corpus striatum and cerebral cortex during pre- and postnatal development. Brain Res. 1156, 31\u201345. https:\/\/doi.org\/10.1016\/j.brainres.2007.04.043 (2007).","journal-title":"Brain Res."},{"key":"99580_CR35","doi-asserted-by":"publisher","first-page":"6853","DOI":"10.1523\/JNEUROSCI.21-17-06853.2001","volume":"21","author":"E Bezard","year":"2001","unstructured":"Bezard, E. et al. Relationship between the appearance of symptoms and the level of nigrostriatal degeneration in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson\u2019s disease. J. Neurosci. 21, 6853\u20136861. https:\/\/doi.org\/10.1523\/JNEUROSCI.21-17-06853.2001 (2001).","journal-title":"J. Neurosci."},{"key":"99580_CR36","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1002\/syn.890210107","volume":"21","author":"SP Hume","year":"1995","unstructured":"Hume, S. P. et al. Effect of L-dopa and 6-hydroxydopamine lesioning on [11C]raclopride binding in rat striatum, quantified using PET. Synapse 21, 45\u201353. https:\/\/doi.org\/10.1002\/syn.890210107 (1995).","journal-title":"Synapse"},{"key":"99580_CR37","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1002\/mds.870080203","volume":"8","author":"JO Rinne","year":"1993","unstructured":"Rinne, J. O. et al. PET study on striatal dopamine D2 receptor changes during the progression of early Parkinson\u2019s disease. Mov. Disord 8, 134\u2013138. https:\/\/doi.org\/10.1002\/mds.870080203 (1993).","journal-title":"Mov. Disord"},{"key":"99580_CR38","doi-asserted-by":"publisher","first-page":"1876","DOI":"10.3390\/biomedicines9121876","volume":"9","author":"K Stokholm","year":"2021","unstructured":"Stokholm, K. et al. \u03b1-Synuclein overexpression increases dopamine D2\/3 receptor binding and immune activation in a model of early Parkinson\u2019s disease. Biomedicines 9, 1876. https:\/\/doi.org\/10.3390\/biomedicines9121876 (2021).","journal-title":"Biomedicines"},{"key":"99580_CR39","doi-asserted-by":"publisher","first-page":"988","DOI":"10.1176\/appi.ajp.2008.07101574","volume":"165","author":"G Grunder","year":"2008","unstructured":"Grunder, G. et al. Brain and plasma pharmacokinetics of aripiprazole in patients with schizophrenia: An [18F]fallypride PET study. Am. J. Psychiatry 165, 988\u2013995. https:\/\/doi.org\/10.1176\/appi.ajp.2008.07101574 (2008).","journal-title":"Am. J. Psychiatry"},{"key":"99580_CR40","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1002\/syn.20904","volume":"65","author":"CC Constantinescu","year":"2011","unstructured":"Constantinescu, C. C., Coleman, R. A., Pan, M. L. & Mukherjee, J. Striatal and extrastriatal microPET imaging of D2\/D3 dopamine receptors in rat brain with [(1)(8)F]fallypride and [(1)(8)F]desmethoxyfallypride. Synapse 65, 778\u2013787. https:\/\/doi.org\/10.1002\/syn.20904 (2011).","journal-title":"Synapse"},{"key":"99580_CR41","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1002\/syn.21867","volume":"69","author":"J Mukherjee","year":"2015","unstructured":"Mukherjee, J. et al. Dopamine D3 receptor binding of (18)F-fallypride: Evaluation using in vitro and in vivo PET imaging studies. Synapse 69, 577\u2013591. https:\/\/doi.org\/10.1002\/syn.21867 (2015).","journal-title":"Synapse"},{"key":"99580_CR42","doi-asserted-by":"publisher","first-page":"2251","DOI":"10.1007\/s00415-014-7302-2","volume":"261","author":"F Niccolini","year":"2014","unstructured":"Niccolini, F., Su, P. & Politis, M. Dopamine receptor mapping with PET imaging in Parkinson\u2019s disease. J. Neurol. 261, 2251\u20132263. https:\/\/doi.org\/10.1007\/s00415-014-7302-2 (2014).","journal-title":"J. Neurol."},{"key":"99580_CR43","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1016\/0006-8993(91)90554-9","volume":"556","author":"JO Rinne","year":"1991","unstructured":"Rinne, J. O., Laihinen, A., Lonnberg, P., Marjamaki, P. & Rinne, U. K. A post-mortem study on striatal dopamine receptors in Parkinson\u2019s disease. Brain Res. 556, 117\u2013122. https:\/\/doi.org\/10.1016\/0006-8993(91)90554-9 (1991).","journal-title":"Brain Res."},{"key":"99580_CR44","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1212\/01.WNL.0000150591.33787.A4","volume":"64","author":"S Zaja-Milatovic","year":"2005","unstructured":"Zaja-Milatovic, S. et al. Dendritic degeneration in neostriatal medium spiny neurons in Parkinson disease. Neurology 64, 545\u2013547. https:\/\/doi.org\/10.1212\/01.WNL.0000150591.33787.A4 (2005).","journal-title":"Neurology"},{"key":"99580_CR45","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1016\/S0166-2236(03)00038-9","volume":"26","author":"E Bezard","year":"2003","unstructured":"Bezard, E., Gross, C. E. & Brotchie, J. M. Presymptomatic compensation in Parkinson\u2019s disease is not dopamine-mediated. Trends Neurosci. 26, 215\u2013221. https:\/\/doi.org\/10.1016\/S0166-2236(03)00038-9 (2003).","journal-title":"Trends Neurosci."},{"key":"99580_CR46","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1016\/j.expneurol.2017.10.002","volume":"298","author":"J Blesa","year":"2017","unstructured":"Blesa, J. et al. Compensatory mechanisms in Parkinson\u2019s disease: Circuits adaptations and role in disease modification. Exp. Neurol. 298, 148\u2013161. https:\/\/doi.org\/10.1016\/j.expneurol.2017.10.002 (2017).","journal-title":"Exp. Neurol."},{"key":"99580_CR47","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1186\/s13287-020-01868-4","volume":"11","author":"JL Goggi","year":"2020","unstructured":"Goggi, J. L. et al. Dopamine transporter neuroimaging accurately assesses the maturation of dopamine neurons in a preclinical model of Parkinson\u2019s disease. Stem Cell Res. Ther. 11, 347. https:\/\/doi.org\/10.1186\/s13287-020-01868-4 (2020).","journal-title":"Stem Cell Res. Ther."},{"key":"99580_CR48","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.neures.2015.07.008","volume":"101","author":"M Ota","year":"2015","unstructured":"Ota, M., Ogawa, S., Kato, K., Masuda, C. & Kunugi, H. Striatal and extrastriatal dopamine release in the common marmoset brain measured by positron emission tomography and [(18)F]fallypride. Neurosci. Res. 101, 1\u20135. https:\/\/doi.org\/10.1016\/j.neures.2015.07.008 (2015).","journal-title":"Neurosci. Res."},{"key":"99580_CR49","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1002\/1098-2396(200010)38:1<71::AID-SYN8>3.0.CO;2-2","volume":"38","author":"BT Christian","year":"2000","unstructured":"Christian, B. T., Narayanan, T. K., Shi, B. & Mukherjee, J. Quantitation of striatal and extrastriatal D-2 dopamine receptors using PET imaging of [(18)F]fallypride in nonhuman primates. Synapse 38, 71\u201379. https:\/\/doi.org\/10.1002\/1098-2396(200010)38:1%3c71::AID-SYN8%3e3.0.CO;2-2 (2000).","journal-title":"Synapse"},{"key":"99580_CR50","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1016\/j.expneurol.2012.01.011","volume":"246","author":"RE Burke","year":"2013","unstructured":"Burke, R. E. & O\u2019Malley, K. Axon degeneration in Parkinson\u2019s disease. Exp. Neurol. 246, 72\u201383. https:\/\/doi.org\/10.1016\/j.expneurol.2012.01.011 (2013).","journal-title":"Exp. Neurol."},{"key":"99580_CR51","doi-asserted-by":"publisher","first-page":"3213","DOI":"10.1073\/pnas.1200575109","volume":"109","author":"M Lundblad","year":"2012","unstructured":"Lundblad, M., Decressac, M., Mattsson, B. & Bjorklund, A. Impaired neurotransmission caused by overexpression of alpha-synuclein in nigral dopamine neurons. Proc. Natl. Acad. Sci. U S A 109, 3213\u20133219. https:\/\/doi.org\/10.1073\/pnas.1200575109 (2012).","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"99580_CR52","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1002\/syn.890070210","volume":"7","author":"J Opacka-Juffry","year":"1991","unstructured":"Opacka-Juffry, J., Ahier, R. G. & Cremer, J. E. Nomifensine-induced increase in extracellular striatal dopamine is enhanced by isoflurane anaesthesia. Synapse 7, 169\u2013171. https:\/\/doi.org\/10.1002\/syn.890070210 (1991).","journal-title":"Synapse"},{"key":"99580_CR53","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1000412","volume":"8","author":"C Kilkenny","year":"2010","unstructured":"Kilkenny, C., Browne, W. J., Cuthill, I. C., Emerson, M. & Altman, D. G. Improving bioscience research reporting: The ARRIVE guidelines for reporting animal research. PLoS Biol. 8, e1000412. https:\/\/doi.org\/10.1371\/journal.pbio.1000412 (2010).","journal-title":"PLoS Biol."},{"issue":"3","key":"99580_CR54","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1016\/0969-8051(94)00117-3","volume":"22","author":"J Mukherjee","year":"1995","unstructured":"Mukherjee, J., Yang, Z. Y., Das, M. K. & Brown, T. Fluorinated benzamide neuroleptics\u2014III. Development of (S)-N-[(1-allyl-2-pyrrolidinyl)methyl]-5-(3-[18F]fluoropropyl)-2,3-dimethoxybenzamide as an improved dopamine D-2 receptor tracer. Nuclear Med. Biol. 22(3), 283\u2013296. https:\/\/doi.org\/10.1016\/0969-8051(94)00117-3 (1995).","journal-title":"Nuclear Med. Biol."},{"key":"99580_CR55","doi-asserted-by":"publisher","first-page":"106","DOI":"10.2967\/jnumed.114.145730","volume":"56","author":"WJ Kuik","year":"2015","unstructured":"Kuik, W. J. et al. In vivo biodistribution of no-carrier-added 6\u201318F-fluoro-3,4-dihydroxy-L-phenylalanine (18F-DOPA), produced by a new nucleophilic substitution approach, compared with carrier-added 18F-DOPA, prepared by conventional electrophilic substitution. J. Nucl. Med. 56, 106\u2013112. https:\/\/doi.org\/10.2967\/jnumed.114.145730 (2015).","journal-title":"J. Nucl. Med."},{"key":"99580_CR56","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1016\/j.nucmedbio.2009.06.007","volume":"36","author":"MN Tantawy","year":"2009","unstructured":"Tantawy, M. N. et al. [(18)F]Fallypride dopamine D2 receptor studies using delayed microPET scans and a modified Logan plot. Nucl. Med. Biol. 36, 931\u2013940. https:\/\/doi.org\/10.1016\/j.nucmedbio.2009.06.007 (2009).","journal-title":"Nucl. Med. Biol."},{"key":"99580_CR57","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1186\/2191-219X-3-69","volume":"3","author":"MD Walker","year":"2013","unstructured":"Walker, M. D. et al. Measuring dopaminergic function in the 6-OHDA-lesioned rat: A comparison of PET and microdialysis. EJNMMI Res. 3, 69. https:\/\/doi.org\/10.1186\/2191-219X-3-69 (2013).","journal-title":"EJNMMI Res."},{"key":"99580_CR58","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1007\/s00702-009-0344-4","volume":"117","author":"K Eggert","year":"2010","unstructured":"Eggert, K. et al. Direct switch from levodopa\/benserazide or levodopa\/carbidopa to levodopa\/carbidopa\/entacapone in Parkinson\u2019s disease patients with wearing-off: efficacy, safety and feasibility\u2013an open-label, 6-week study. J. Neural Trans. (Vienna) 117, 333\u2013342. https:\/\/doi.org\/10.1007\/s00702-009-0344-4 (2010).","journal-title":"J. Neural Trans. (Vienna)"},{"key":"99580_CR59","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1186\/2191-219X-1-25","volume":"1","author":"K Kyono","year":"2011","unstructured":"Kyono, K. et al. Use of [18F]FDOPA-PET for in vivo evaluation of dopaminergic dysfunction in unilaterally 6-OHDA-lesioned rats. EJNMMI Res. 1, 25. https:\/\/doi.org\/10.1186\/2191-219X-1-25 (2011).","journal-title":"EJNMMI Res."},{"key":"99580_CR60","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1111\/jnc.14016","volume":"141","author":"G Becker","year":"2017","unstructured":"Becker, G. et al. Comparative assessment of 6-[(18) F]fluoro-L-m-tyrosine and 6-[(18) F]fluoro-L-dopa to evaluate dopaminergic presynaptic integrity in a Parkinson\u2019s disease rat model. J. Neurochem. 141, 626\u2013635. https:\/\/doi.org\/10.1111\/jnc.14016 (2017).","journal-title":"J. Neurochem."},{"key":"99580_CR61","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.neuroimage.2019.05.016","volume":"199","author":"KK Osen","year":"2019","unstructured":"Osen, K. K., Imad, J., Wennberg, A. E., Papp, E. A. & Leergaard, T. B. Waxholm Space atlas of the rat brain auditory system: Three-dimensional delineations based on structural and diffusion tensor magnetic resonance imaging. Neuroimage 199, 38\u201356. https:\/\/doi.org\/10.1016\/j.neuroimage.2019.05.016 (2019).","journal-title":"Neuroimage"},{"key":"99580_CR62","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1016\/j.neuroimage.2014.04.001","volume":"97","author":"EA Papp","year":"2014","unstructured":"Papp, E. A., Leergaard, T. B., Calabrese, E., Johnson, G. A. & Bjaalie, J. G. Waxholm space atlas of the sprague dawley rat brain. Neuroimage 97, 374\u2013386. https:\/\/doi.org\/10.1016\/j.neuroimage.2014.04.001 (2014).","journal-title":"Neuroimage"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-99580-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-99580-x","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-99580-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T12:39:51Z","timestamp":1746621591000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-99580-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,7]]},"references-count":62,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["99580"],"URL":"https:\/\/doi.org\/10.1038\/s41598-025-99580-x","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,7]]},"assertion":[{"value":"14 August 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 April 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 May 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All applicable international, national, and\/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted. All experiments and procedures conducted on animals were carried out in accordance with United Kingdom Home Office regulations under the Animal (Scientific Procedures) Act (1986), and were approved by the local ethical review board of the Department of Physiology, Anatomy and Genetics at the University of Oxford.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}],"article-number":"15943"}}