Dopamine‐dependent motor learning: Insight into levodopa's long‐duration response

Beeler, Jeff A.; Cao, Zhen; Kheirbek, Mazen A.; Ding, Yunmin; Koranda, Jessica L.; Murakami, Mari; Kang, Un Jung; Zhuang, Xiaoxi

doi:10.1002/ana.21947

Cited by 81 publications

(94 citation statements)

References 40 publications

(122 reference statements)

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“…Interestingly, the CR by the L-dopa-trained mice did not vanish immediately when animals were retested in their dopamine-deficient state but, rather, faded over several days, similar to extinction-like decline. A similar observation was made in a different model of dopamine deficiency in the context of motor learning by Beeler et al (33), who showed that cessation of L-dopa treatment in Pitx3 −/− mice resulted in a gradual performance decline. They suggested that this poor performance might actually have a learning component and that perhaps poor motor performance in Parkinson disease is learned (33).…”

Section: Discussionsupporting

confidence: 75%

Dopamine dependency for acquisition and performance of Pavlovian conditioned response

Darvas¹,

Wunsch

Gibbs³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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During Pavlovian conditioning, pairing of a neutral conditioned stimulus (CS) with a reward leads to conditioned reward-approach responses (CRs) that are elicited by presentation of the CS. CR behaviors can be sign tracking, in which animals engage the CS, or goal tracking, in which animals go to the reward location. We investigated CR behaviors in mice with only ∼5% of normal dopamine in the striatum using a Pavlovian conditioning paradigm. These mice had severely impaired acquisition of the CR, which was ameliorated by pharmacological restoration of dopamine synthesis with L-dopa. Surprisingly, after they had learned the CR, its expression decayed only gradually in following sessions that were conducted without L-dopa treatment. To assess specific contributions of dopamine signaling in the dorsal or ventral striatum, we performed virus-mediated restoration of dopamine synthesis in completely dopamine-deficient (DD) mice. Mice with dopamine signaling only in the dorsal striatum did not acquire a CR, whereas mice with dopamine signaling only in in the ventral striatum acquired a CR. The CR in mice with dopamine signaling only in the dorsal striatum was restored by subjecting the mice to instrumental training in which they had to interact with the CS to obtain rewards. We conclude that dopamine is essential for learning and performance of CR behavior that is predominantly goal tracking. Furthermore, although dopamine signaling in the ventral striatum is sufficient to support a CR, dopamine signaling only in the dorsal striatum can also support a CR under certain circumstances.

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Section: Discussionsupporting

confidence: 75%

Dopamine dependency for acquisition and performance of Pavlovian conditioned response

Darvas¹,

Wunsch

Gibbs³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Indeed, complex movements have to be learned and practiced repeatedly to improve their execution. Nigrostriatal dopamine is an important modulator of these mechanisms, which are impaired following the partial loss or disruption of this pathway (Akita et al, 2006;Beeler et al, 2010;Ogura et al, 2005;Willuhn and Steiner, 2008). In this context, plasticity at glutamatergic corticostriatal synapses within the dorsal striatum has been implicated in motor learning (Dang et al, 2006;Pisani et al, 2005;Yin et al, 2009) and is regulated by dopamine (Calabresi et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Control of the Nigrostriatal Dopamine Neuron Activity and Motor Function by the Tail of the Ventral Tegmental Area

Bourdy

Sánchez-Catalán

Kaufling

et al. 2014

Neuropsychopharmacol

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Midbrain dopamine neurons are implicated in various psychiatric and neurological disorders. The GABAergic tail of the ventral tegmental area (tVTA), also named the rostromedial tegmental nucleus (RMTg), displays dense projections to the midbrain and exerts electrophysiological control over dopamine cells of the VTA. However, the influence of the tVTA on the nigrostriatal pathway, from the substantia nigra pars compacta (SNc) to the dorsal striatum, and on related functions remains to be addressed. The present study highlights the role played by the tVTA as a GABA brake for the nigrostriatal system, demonstrating a critical influence over motor functions. Using neuroanatomical approaches with tract tracing and electron microscopy, we reveal the presence of a tVTA-SNc-dorsal striatum pathway. Using in vivo electrophysiology, we prove that the tVTA is a major inhibitory control center for SNc dopamine cells. Using behavioral approaches, we demonstrate that the tVTA controls rotation behavior, motor coordination, and motor skill learning. The motor enhancements observed after ablation of the tVTA are in this regard comparable with the performance-enhancing properties of amphetamine, a drug used in doping. These findings demonstrate that the tVTA is a major GABA brake for nigral dopamine systems and nigrostriatal functions, and they raise important questions about how the tVTA is integrated within the basal ganglia circuitry. They also warrant further research on the tVTA's role in motor and dopamine-related pathological contexts such as Parkinson's disease.

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“…We reported that dopamine-dependent motor learning in a mouse model of PD produces the same phenomenon as LDR. 3 Learning motor tasks was dependent on both dopamine and task-training and occurred over a few days. In the absence of dopamine, task-training resulted in development of aberrant learning, leading to deterioration of performance over a few days.…”

Section: Discussionmentioning

confidence: 99%

Activity enhances dopaminergic long-duration response in Parkinson disease

Kang

2012

Neurology

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Objective:We tested the hypothesis that dopamine-dependent motor learning mechanism underlies the long-duration response to levodopa in Parkinson disease (PD) based on our studies in a mouse model. By data-mining the motor task performance in dominant and nondominant hands of the subjects in a double-blind randomized trial of levodopa therapy, the effects of activity and dopamine therapy were examined. Methods:We data-mined the Earlier versus Later Levodopa Therapy in Parkinson's Disease (ELL-DOPA) study published in 2005 and performed statistical analysis comparing the effects of levodopa and dominance of handedness over 42 weeks. Results:The mean change in finger-tapping counts from baseline before the initiation of therapy to predose at 9 weeks and 40 weeks increased more in the dominant compared to nondominant hand in levodopa-treated subjects in a dose-dependent fashion. There was no significant difference in dominant vs nondominant hands in the placebo group. The short-duration response assessed by the difference of postdose performance compared to predose performance at the same visit did not show any significant difference between dominant vs nondominant hands.Conclusions: Active use of the dominant hand and dopamine replacement therapy produces synergistic effect on long-lasting motor task performance during "off " medication state. Such effect was confined to dopamine-responsive symptoms and not seen in dopamine-resistant symptoms such as gait and balance. We propose that long-lasting motor learning facilitated by activity and dopamine is a form of disease modification that is often seen in trials of medications that have symptomatic effects. Neurology Long-duration response (LDR) in Parkinson disease (PD) pharmacologic therapy develops over days to weeks with chronic use of the drug, and gradually decays after the drug is stopped. LDR is distinct from short-duration response (SDR) that parallels the half-life of the drug (hours). LDR is a more beneficial and durable component of dopaminergic therapy without accompanying dyskinesia and motor fluctuations, 1,2 but its underlying mechanism is poorly understood. We reported that dopamine-dependent motor learning in a mouse model of PD produces the same phenomenon as LDR.3 Learning motor tasks was dependent on both dopamine and task-training and occurred over a few days. In the absence of dopamine, task-training resulted in development of aberrant learning, leading to deterioration of performance over a few days.Therefore, we hypothesized that LDR is facilitated by a combination of active training and dopamine to a greater magnitude than achievable by either one alone.

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Dopamine‐dependent motor learning: Insight into levodopa's long‐duration response

Cited by 81 publications

References 40 publications

Dopamine dependency for acquisition and performance of Pavlovian conditioned response

Dopamine dependency for acquisition and performance of Pavlovian conditioned response

Control of the Nigrostriatal Dopamine Neuron Activity and Motor Function by the Tail of the Ventral Tegmental Area

Activity enhances dopaminergic long-duration response in Parkinson disease

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