Dopamine-dependent motor learning: insight into levodopa's long-duration response.
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.


CONCLUSIONS
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.
Beeler
Jeff A
JA
Department of Neurobiology, University of Chicago, Chicago, IL 60637, USA. jabeeler@uchicago.edu
Cao
Zhen Fang Huang
ZF
Kheirbek
Mazen A
MA
Ding
Yunmin
Y
Koranda
Jessica
J
Murakami
Mari
M
Kang
Un Jung
UJ
Zhuang
Xiaoxi
X
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001552:Benzazepines / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018398:Homeodomain Proteins; D007858:Learning / Q000187:drug effects*; D007980:Levodopa / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D018345:Mice, Knockout; D009048:Motor Skills / Q000187:drug effects*; D009069:Movement Disorders / Q000188:drug therapy* / Q000235:genetics; D011930:Reaction Time / Q000187:drug effects; D045442:Rotarod Performance Test / Q000379:methods; D013997:Time Factors; D014157:Transcription Factors / Q000172:deficiency
D001552:Benzazepines; D015259:Dopamine Agents; D018398:Homeodomain Proteins; C534628:SCH 23390; D014157:Transcription Factors; C433629:homeobox protein PITX3; D007980:Levodopa; D004298:Dopamine