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

Abstract

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.

FIGURE 1

Rotarod performance with and without L-dopa treatment. Mice were trained on the rotarod with either saline or L-dopa for 5 sessions (sessions 1–5). After a 3-day treatment discontinuation break, the mice were tested without treatment (session 6). (A) Latency to fall in each trial. (B) Average latency to fall during each session. n = 6 per genotype/treatment. HET = heterozygote; HOM = homozygote.

FIGURE 2

Performance after discontinuation of L-dopa. The same mice from Figure 1 were retrained on the rotarod with either saline or L-dopa for 1 session (session 7). After a 5-day treatment discontinuation break, mice were run for 3 sessions without any treatment (sessions 8–10). (A) Latency to fall in each trial. (B) Average latency to fall during each session. n = 6 per genotype/treatment. HET = heterozygote; HOM = homozygote.

FIGURE 3

Effect of elapsed time after discontinuation of L-dopa on rotarod performance. PITx3(−/−) mice were trained with L-dopa for 7 sessions (sessions 1–7). One group was tested without treatment 3 days following discontinuation of L-dopa (red circles, sessions 8 –11), another group was tested 10 days after L-dopa discontinuation (blue circles, sessions 8 –11), and a final group was tested with L-dopa treatment after a 10-day suspension of L-dopa (black circles, sessions 8 –11). (A) Latency to fall in each trial. (B) Average latency to fall during each session. n = 12 for the 3-day interval group; n = 6 for 10-day interval groups.

FIGURE 4

Time-course of L-dopa treatment effects. PITx3(−/−) mice were given L-dopa or saline injections at different time points (1 hour, 6 hours, or 12 hours) before training for 3 days. (A) Latency to fall in each trial. (B) Average latency to fall during each session (n = 6 per treatment). (C) Dopamine (DA) content in dorsal striatum of L-dopa–naive PITx3(−/−) animals, PITx3(−/−) animals receiving an acute L-dopa injection (1 hour prior to sample collection), and PITx3(−/−) animals receiving chronic L-dopa treatment for 7 days and treatment cessation for either 3 or 10 days. n = 6 per treatment.

FIGURE 5

Task-specificity of loss of performance. PITx3(−/−) mice were trained for 7 session with L-dopa (last session of training, session 7, is shown). The No Task group was given a 10-day break without rotarod testing nor L-dopa injections. The Task group was also given a 10-day break without rotarod test nor L-dopa injections, but mice were allowed to run on a treadmill every day during those 10 days. Rotarod performance was tested after the 10-day break without L-dopa (sessions 8–11) for 4 consecutive days. (A) Latency to fall in each trial. (B) Average latency to fall during each session. n = 6 per treatment.

FIGURE 6

L-Dopa administration following training sessions. Mice were trained for 7 sessions with either saline or L-dopa administered following the last trial of each session. (A) Latency to fall in each trial. (B) Average latency to fall during each session. n = 5 per genotype/treatment. HET = heterozygote; HOM = homozygote.

FIGURE 7

Effect of D1 and D2 antagonists on rotarod performance in wild-type animals. Animals were trained on the rotarod for 12 days without injections (the last training session, session 12, is shown). Animals were then given either a D1 blocker (SCH 23390) or a D2 blocker (eticlopride) and tested on the rotarod for 5 consecutive days (sessions 13–17). (A) Latency to fall in each trial (eticlopride). (B) Average latency to fall during each session (eticlopride). (C) Latency to fall in each trial (SCH 23390). (D) Average latency to fall during each session (SCH 23390).

FIGURE 8

Schematic comparing LDR in L-dopa treatment of Parkinson disease (PD) and effects of L-dopa treatment on rotarod performance in PITx3-deficient mice. (A) Short-duration response (SDR) (gray) and long-duration response (LDR) (blue) during the progression of PD. As the disease progresses, baseline performance (dashed line) decreases. In addition, SDR increases in magnitude throughout the disease, although this is due to the progressive decline in baseline performance of patients. LDR, however, decreases in duration as the disease progresses.^– (B) SDR and LDR in a single treatment period in PD. Before L-dopa treatment, baseline performance (dashed line) is significantly lower in PD patients than in normal patients (solid line). With L-dopa treatment, SDR is observed after each L-dopa dose (gray shading). After L-dopa treatment discontinuation, performance is not immediately lost, but displays a gradual decline due to LDR (blue shading).^,,,, (C) Performance on rotarod task of PITx3(−/−) mice during L-dopa treatment and following discontinuation. (D) Hypothesized SDR and LDR in PITx3-deficient mice. Before L-dopa treatment, baseline performance of PITx3(−/−) (dashed line) on the rotarod task is significantly lower than that of PITx3(+/−) (solid line). With each L-dopa injection, PITx3(−/−) display SDR (gray shading), which rescues performance on the rotarod. Multiple training sessions with L-dopa administration allow learning to occur, as observed in gradual improvement across sessions (blue shading). After L-dopa treatment is discontinued, performance gradually degrades, similarly to the decline in LDR observed in patients.