Dopamine-dependent motor learning: insight into levodopa's long-duration response
Open accessAbstract
OBJECTIVE: Dopamine (DA) is critical for motor performance, motor learning, and corticostriatal plasticity. The relationship between motor performance and learning, and the role of DA in the mediation of them, however, remain unclear. METHODS: To examine this question, we took advantage of PITx3-deficient mice (aphakia mice), in which DA in the dorsal striatum is reduced by 90%. PITx3-deficient mice do not display obvious motor deficits in their home cage, but are impaired in motor tasks that require new motor skills. We used the accelerating rotarod as a motor learning task. RESULTS: We show that the deficiency in motor skill learning in PITx3(-/-) is dramatic and can be rescued with levodopa treatment. In addition, cessation of levodopa treatment after acquisition of the motor skill does not result in an immediate drop in performance. Instead, there is a gradual decline of performance that lasts for a few days, which is not related to levodopa pharmacokinetics. We show that this gradual decline is dependent on the retesting experience. INTERPRETATION: This observation resembles the long-duration response to levodopa therapy in its slow buildup of improvement after the initiation of therapy and gradual degradation. We hypothesize that motor learning may play a significant, underappreciated role in the symptomatology of Parkinson disease as well as in the therapeutic effects of levodopa. We suggest that the important, yet enigmatic long-duration response to chronic levodopa treatment is a manifestation of rescued motor learning.
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Eight weeks of treadmill exercise in early Parkinson's disease was accompanied by an increase in DA-D2R binding potential within the dorsal striatum.
“Fisher and colleagues reported that 8 weeks of treadmill exercise was accompanied by an increase in DA-D2R binding potential within the dorsal striatum of individuals with early stage PD 48.”
From Exercise-enhanced neuroplasticity targeting motor and cognitive circuitry in Parkinson's disease (2013) · cites this paper as [48]
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Cites
Levodopa and the Progression of Parkinson's Disease
The Parkinson Study Group (2004) · New England Journal of Medicine · doi:10.1056/nejmoa033447 · Cited by 1,844 · see citing works
Learning and Memory Functions of the Basal Ganglia
Packard, M. G., & Knowlton, B. J. (2002) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.25.112701.142937 · Cited by 1,717 · see citing works
6-Hydroxy-dopamine induced degeneration of central monoamine neurons.
Ungerstedt, U. (1968) · European Journal of Pharmacology · doi:10.1016/0014-2999(68)90164-7 · Cited by 1,516 · see citing works
Dichotomous dopaminergic control of striatal synaptic plasticity
Shen, W., Flajolet, M., Greengard, P., & Surmeier, D. J. (2008) · Science · doi:10.1126/science.1160575 · Cited by 1,190 · see citing works
Dynamic reorganization of striatal circuits during the acquisition and consolidation of a skill
Yin, H. H., Mulcare, S. P., Hilário, M. R. F., Clouse, E., Holloway, T., Davis, M. I., Hansson, A. C., Lovinger, D. M., & Costa, R. M. (2009) · Nature Neuroscience · doi:10.1038/nn.2261 · Cited by 818 · see citing works
Dopamine-deficient mice are severely hypoactive, adipsic, and aphagic
Zhou, Q.-Y., & Palmiter, R. D. (1995) · Cell · doi:10.1016/0092-8674(95)90145-0 · Cited by 731 · see citing works
Bergman, H., Feingold, A., Nini, A., Raz, A., Slovin, H., Abeles, M., & Vaadia, E. (1998) · Trends in Neurosciences · doi:10.1016/s0166-2236(97)01151-x · Cited by 630 · see citing works
Behavioral phenotyping of the MPTP mouse model of Parkinson's disease
Sedelis, M., Schwarting, R. K. W., & Huston, J. P. (2001) · Behavioural Brain Research · doi:10.1016/s0166-4328(01)00309-6 · Cited by 434 · see citing works
Pitx3 is required for development of substantia nigra dopaminergic neurons
Nunes, I., Tovmasian, L. T., Silva, R. M., Burke, R. E., & Goff, S. P. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0230529100 · Cited by 385 · see citing works
DATATOP: A Multicenter Controlled Clinical Trial in Early Parkinson's Disease
(1989) · Archives of Neurology · doi:10.1001/archneur.1989.00520460028009 · Cited by 357 · see citing works
Pitx3 is required for motor activity and for survival of a subset of midbrain dopaminergic neurons
van den Munckhof, P., Luk, K. C., Ste‐Marie, L., Montgomery, J. A., Blanchet, P. J., Sadikot, A. F., & Drouin, J. (2003) · Development · doi:10.1242/dev.00464 · Cited by 300 · see citing works
Miyachi, S., Hikosaka, O., & Lu, X. (2002) · Experimental Brain Research · doi:10.1007/s00221-002-1213-7 · Cited by 262 · see citing works
Selective loss of dopaminergic neurons in the substantia nigra of Pitx3-deficient aphakia mice
Hwang, D. (2003) · Molecular Brain Research · doi:10.1016/s0169-328x(03)00162-1 · Cited by 257 · see citing works
Serial reaction time learning and Parkinson's disease: Evidence for a procedural learning deficit
Jackson, G. M., Jackson, S. R., Harrison, J., Henderson, L., & Christopher Kennard, C. (1995) · Neuropsychologia · doi:10.1016/0028-3932(95)00010-z · Cited by 249 · see citing works
Chang, J. W., Wachtel, S. R., Young, D., & Kang, U. J. (1999) · Neuroscience · doi:10.1016/s0306-4522(98)00217-6 · Cited by 248 · see citing works
Self-citationMuenter, M. D., & Tyce, G. M. (1971) · Mayo Clinic Proceedings · doi:10.1016/s0025-6196(25)07667-0 · Cited by 248 · see citing works
Disrupted motor learning and long-term synaptic plasticity in mice lacking NMDAR1 in the striatum
Dang, M. T., Yokoi, F., Yin, H. H., Lovinger, D. M., Wang, Y., & Li, Y. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0601758103 · Cited by 241 · see citing works
Is implicit sequence learning impaired in Parkinson's disease? A meta-analysis.
Siegert, R. J., Taylor, K. D., Weatherall, M., & Abernethy, D. A. (2006) · Neuropsychology · doi:10.1037/0894-4105.20.4.490 · Cited by 177 · see citing works
Hwang, D., Fleming, S. M., Ardayfio, P. A., Moran‐Gates, T., Kim, H.-S., Tarazi, F. I., Chesselet, M., & Kim, K. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.3718-04.2005 · Cited by 171 · see citing works
Tedroff, J., Pedersen, M., Sm, A., Hartvig, P., Jacobsson, G., & Långström, B. (1996) · Neurology · doi:10.1212/wnl.46.5.1430 · Cited by 162 · see citing works
The early diagnosis of parkinson's disease
Brooks, D. J. (1998) · Annals of Neurology · doi:10.1002/ana.410440704 · Cited by 157 · see citing works
Procedural motor learning in Parkinson's disease
Krebs, H. I., Hogan, N., Hening, W., Adamovich, S. V., & Howard Poizner, A. (2001) · Experimental Brain Research · doi:10.1007/s002210100871 · Cited by 135 · see citing works
Reynolds, J. N. J., & Wickens, J. R. (2000) · Neuroscience · doi:10.1016/s0306-4522(00)00273-6 · Cited by 131 · see citing works
Evolution of the response to levodopa during the first 4 years of therapy
Nutt, J. G., Carter, J. H., Lea, E. S., & Sexton, G. J. (2002) · Annals of Neurology · doi:10.1002/ana.10189 · Cited by 130 · see citing works
Long-duration response to levodopa
Nutt, J. G., Carter, J. H., & Woodward, W. R. (1995) · Neurology · doi:10.1212/wnl.45.8.1613 · Cited by 109 · see citing works
The differential effect of PD and normal aging on early explicit sequence learning
Ghilardi, M. F., Eidelberg, D., Silvestri, G., & Ghez, C. P. (2003) · Neurology · doi:10.1212/01.wnl.0000059545.69089.ee · Cited by 103 · see citing works
Short‐ and long‐duration responses to levodopa during the first year of levodopa therapy
Nutt, J. G., Carter, J. H., Houten, L. V., & Woodward, W. R. (1997) · Annals of Neurology · doi:10.1002/ana.410420311 · Cited by 103 · see citing works
Apomorphine responses in parkinson's disease and the pathogenesis of motor complications
Metman, L. V., Locatelli, E. R., Bravi, D., et al. (1997) · Neurology · doi:10.1212/wnl.48.2.369 · Cited by 94 · see citing works
Behrman, A. L., Cauraugh, J. H., & Light, K. E. (2000) · Journal of the Neurological Sciences · doi:10.1016/s0022-510x(00)00267-7 · Cited by 90 · see citing works
Ogura, T., Ogata, M., Akita, H., Jitsuki, S., Akiba, L., Noda, K., Hoka, S., & Saji, M. (2005) · Neuroscience Research · doi:10.1016/j.neures.2004.12.006 · Cited by 71 · see citing works
Ding, Y., Restrepo, J., Won, L., et al. (2007) · Neurobiology of Disease · doi:10.1016/j.nbd.2007.03.013 · Cited by 70 · see citing works
Self-citationZappia, M., Colao, R., Montesanti, R., et al. (1997) · Annals of Neurology · doi:10.1002/ana.410420217 · Cited by 67 · see citing works
The subacute levodopa test for evaluating long‐duration response in parkinson's disease
Quattrone, A., Zappia, M., Aguglia, U., Branca, D., Colao, R., Montesanti, R., Nicoletti, G., Palmieri, A., Parlato, G., & Rizzo, M. (1995) · Annals of Neurology · doi:10.1002/ana.410380308 · Cited by 65 · see citing works
Ardayfio, P. A., Moon, J., Leung, K. K. A., et al. (2008) · Neurobiology of Disease · doi:10.1016/j.nbd.2008.05.017 · Cited by 50 · see citing works
Wiecki, T. V., Riedinger, K., von Ameln-Mayerhofer, A., Schmidt, W., & Frank, M. J. (2009) · Psychopharmacology · doi:10.1007/s00213-008-1457-4 · Cited by 46 · see citing works
Loss of Cocaine Locomotor Response in Pitx3-Deficient Mice Lacking a Nigrostriatal Pathway
Beeler, J. A., Cao, Z. F. H., Kheirbek, M. A., & Zhuang, X. (2008) · Neuropsychopharmacology · doi:10.1038/npp.2008.117 · Cited by 45 · see citing works
Self-citationMolecular and cellular alterations in the Pitx3-deficient midbrain dopaminergic system
Smits, S. M., Mathon, D. S., Burbach, J. P. H., Ramakers, G. M. J., & Smidt, M. P. (2005) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2005.07.018 · Cited by 33 · see citing works
Kas, M. J., Vanderlinden, A., Oppelaar, H., et al. (2007) · Behavioural Brain Research · doi:10.1016/j.bbr.2007.08.032 · Cited by 19 · see citing works
Motor deficits and altered striatal gene expression in aphakia (ak) mice
Singh, B., Wilson, J. H., Vasavada, H. H., Guo, Z., Allore, H. G., & Zeiss, C. J. (2007) · Brain Research · doi:10.1016/j.brainres.2007.09.006 · Cited by 13 · see citing works
The long duration response to levodopa in Parkinson's disease
Madden, D. L., Morris, J. G., Graham, S. J., et al. (1995) · Journal of Clinical Neuroscience · doi:10.1016/0967-5868(95)90030-6 · Cited by 3 · see citing works
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Exercise-enhanced neuroplasticity targeting motor and cognitive circuitry in Parkinson's disease
Petzinger, G. M., Fisher, B. E., McEwen, S., Beeler, J. A., Walsh, J. P., & Jakowec, M. W. (2013) · The Lancet Neurology · doi:10.1016/s1474-4422(13)70123-6 · Cited by 798 · see citing works
Self-citationWu, J., Kung, J., Dong, J., Chang, L., Xie, C., Habib, A., Hawes, S., Yang, N., Chen, V., Liu, Z., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.06.095 · Cited by 87 · see citing works
- Authors
- Beeler, J. A., Cao, Z. F. H., Kheirbek, M. A., Ding, Y., Koranda, J., Murakami, M., Kang, U. J., & Zhuang, X.
- Affiliations
- University of Chicago (US)
- Corresponding author
- Beeler, Jeff A.
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2010-04-26
- Volume
- 67
- Issue
- 5
- Pages
- 639-647
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC3129617
- OpenAlex
- W2026632475
- Cited by
- 104
- References
- 40
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 9 · 2023: 5 · 2022: 6 · 2021: 4 · 2020: 4 · 2019: 4 · 2018: 5 · 2017: 6 · 2016: 7 · 2015: 3 · 2014: 7 · 2013: 11 · 2012: 9
- FWCI
- 4.47
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Parkinson Disease Association
- National Institutes of Health
- National Institute on Drug Abuse (DA025875, R01DA025875)
- National Institute of Neurological Disorders and Stroke (NS064865, R01NS064865)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cognitive Neuroscience › Motor Control and Adaptation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- dopamine, motor learning, levodopa, Pitx3, dorsal striatum, Parkinson's disease, motor skill learning
- MeSH terms
- Animals, Behavior, Animal, Benzazepines, Dopamine, Learning, Levodopa, Motor Skills, Movement Disorders, Reaction Time, Time Factors, Transcription Factors, Dopamine Agents, Mice, Knockout, Homeodomain Proteins, Rotarod Performance Test, Mice
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