Genetic variation in the human brain dopamine system influences motor learning and its modulation by L-Dopa

Abstract

Dopamine is important to learning and plasticity. Dopaminergic drugs are the focus of many therapies targeting the motor system, where high inter-individual differences in response are common. The current study examined the hypothesis that genetic variation in the dopamine system is associated with significant differences in motor learning, brain plasticity, and the effects of the dopamine precursor L-Dopa. Skilled motor learning and motor cortex plasticity were assessed using a randomized, double-blind, placebo-controlled, crossover design in 50 healthy adults during two study weeks, one with placebo and one with L-Dopa. The influence of five polymorphisms with established effects on dopamine neurotransmission was summed using a gene score, with higher scores corresponding to higher dopaminergic neurotransmission. Secondary hypotheses examined each polymorphism individually. While training on placebo, higher gene scores were associated with greater motor learning (p = .03). The effect of L-Dopa on learning varied with the gene score (gene score*drug interaction, p = .008): participants with lower gene scores, and thus lower endogenous dopaminergic neurotransmission, showed the largest learning improvement with L-Dopa relative to placebo (p<.0001), while L-Dopa had a detrimental effect in participants with higher gene scores (p = .01). Motor cortex plasticity, assessed via transcranial magnetic stimulation (TMS), also showed a gene score*drug interaction (p = .02). Individually, DRD2/ANKK1 genotype was significantly associated with motor learning (p = .02) and its modulation by L-Dopa (p<.0001), but not with any TMS measures. However, none of the individual polymorphisms explained the full constellation of findings associated with the gene score. These results suggest that genetic variation in the dopamine system influences learning and its modulation by L-Dopa. A polygene score explains differences in L-Dopa effects on learning and plasticity most robustly, thus identifying distinct biological phenotypes with respect to L-Dopa effects on learning and plasticity. These findings may have clinical applications in post-stroke rehabilitation or the treatment of Parkinson's disease.

Conflict of interest statement

Competing Interests: Dr. Cramer has served as a consultant to GlaxoSmithKline, Pfizer, and Microtransponder. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. The experimental protocol.

Figure 2. The Marble Navigation Task used to measure skilled motor learning.

(A) Participants view the computer screen to see where to move the marble. (B) The MNT board used for week 1. (C) A novel version of the same MNT board was used for week 2.

Figure 3. Motor learning data across each week.

The average time to completion of each 100-target trial for days 1–3 (4 trials per day) on the MNT for (A) week 1 and (B) week 2. Mean ± SEM.

Figure 4. Effect of L-Dopa on skilled motor learning varied with gene score.

Below gene score = 2, L-Dopa provides better learning, and above gene score = 2, Placebo provides better learning. Values are derived from the mixed-effects model and reflect the percent improvement from the reference condition of gene score = 0 during the placebo week, using the average value for all covariates.