Title Genetic Variation in the Human Brain Dopamine System Influences Motor Learning and Its Modulation by L-Dopa Permalink

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. Citation: Pearson-Fuhrhop KM, Minton B, Acevedo D, Shahbaba B, Cramer SC (2013) Genetic Variation in the Human Brain Dopamine System Influences Motor Learning and Its Modulation by L-Dopa. PLoS ONE 8(4): e61197. doi:10.1371/journal.pone. 0061197 Editor: Veronique Sgambato-Faure, INSERM/CNRS, France Received October 9, 2012; Accepted March 7, 2013; Published April 17, 2013 Copyright: 2013 Pearson-Fuhrhop et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This study was supported by the American Heart Association, and grants R01 NS058755 and 5M011 RR-00827-29 from National Institutes of Health. The project was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1 TR000153. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 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. * E-mail: scramer@uci.edu