These authors contributed equally to this work.
Dopamine-dependent motor learning: Insight into levodopa's long-duration response
Article first published online: 23 DEC 2009
Copyright © 2010 American Neurological Association
Annals of Neurology
Volume 67, Issue 5, pages 639–647, May 2010
How to Cite
Beeler, J. A., Cao, Z. F. H., Kheirbek, M. A., Ding, Y., Koranda, J., Murakami, M., Kang, U. J. and Zhuang, X. (2010), Dopamine-dependent motor learning: Insight into levodopa's long-duration response. Ann Neurol., 67: 639–647. doi: 10.1002/ana.21947
- Issue published online: 26 APR 2010
- Article first published online: 23 DEC 2009
- Manuscript Accepted: 3 DEC 2009
- Manuscript Revised: 2 DEC 2009
- Manuscript Received: 8 JUL 2009
- NIH NIDA. Grant Number: DA025875
- NIH NINDS. Grant Number: NS064865
- American Parkinson's Disease Association Center for Advanced Research
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.
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.
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.
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. ANN NEUROL 2010;67:639–647