Treadmill Exercise Attenuates L-DOPA-Induced Dyskinesia and Increases Striatal Levels of Glial Cell-Derived Neurotrophic Factor (GDNF) in Hemiparkinsonian Mice Ana E. Speck 1 & Marissa G. Schamne 2 & Aderbal S. Aguiar Jr 1,3 & Rodrigo A. Cunha 4,5 & Rui D. Prediger 1,2 Received: 27 April 2018 /Accepted: 23 July 2018 # Springer Science+Business Media, LLC, part of Springer Nature 2018 Abstract Exercise can act as a disease-modifying agent in Parkinson’ s disease (PD), and we have previously demonstrated that voluntary exercise in running wheels during 2 weeks normalizes striatopallidal dopaminergic signaling and prevents the development of L- DOPA-induced dyskinesia (LID) in C57BL/6 mice. We now tested whether LID in Swiss albino mice could be attenuated by treadmill-controlled exercise alone or in combination with the reference antidyskinetic drug amantadine. The daily intraperitoneal (i.p.) treatment with three different doses of L-DOPA/benserazide (30/12.5, 50/25, or 70/35 mg/kg) during 3 weeks induced increasing levels of LID scores in hemiparkinsonian Swiss albino mice previously lesioned with a unilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA, 10 μg). Then, we addressed the antidyskinetic effects of treadmill-controlled exercise by comparing LID, induced by L-DOPA/benserazide (50/25 mg/kg, i.p.) during 4 weeks, in sedentary and daily exercised mice. Exercise reduced LID and improved motor skills of dyskinetic mice, as indicated by decreased contralateral bias, increase in maximal load test, and latency to fall in rotarod. The antidyskinetic effect of amantadine (60 mg/kg, i.p.) was only observed in sedentary mice, indicating the absence of synergistic antidyskinetic effect of the combination of treadmill exercise plus aman- tadine. Finally, Western blot analysis unraveled an ability of exercise to increase the striatal immunocontent of glial cell-derived neurotrophic factor (GDNF), apart from normalizing striatal levels of tyrosine hydroxylase. These findings show that controlled treadmill exercise attenuates LID and provide the first indication that the antidyskinetic effects of treadmill exercise may involve increased striatal GDNF levels. Keywords Exercise . Treadmill . Dyskinesia . L-DOPA . GDNF . Parkinson’ s disease . 6-OHDA Introduction The development of L-DOPA-induced dyskinesia (LID), also known as abnormal involuntary movements (AIMs), constitutes a major limitation in the long-term pharmacological treatment of Parkinson’ s disease (PD) patients. About 90% of PD patients develop LID within a decade of onset of L-DOPA treatment, representing an important socioeconomic cause of distress [1]. The exact molecular mechanisms associated with LID develop- ment remain unknown. The prime candidates are alterations in dopaminergic neurotransmission, described in animal models of PD, such as dysregulation in presynaptic control of vesicular dopamine (DA) loading and DA release, as well as decreased DA reuptake by DA transporter (DAT) [1, 2]. Previous findings indicated that exercise prevents the loss of dopaminergic neurons and alterations in dopaminergic neu- rotransmission in the nigrostriatal pathway in rodent models of PD [3–6]. Our group previously reported that voluntary Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12035-018-1278-3) contains supplementary material, which is available to authorized users. * Rui D. Prediger ruidsp@hotmail.com; rui.prediger@ufsc.br 1 Graduate Program of Neuroscience, Center of Biological Sciences, Federal University of Santa Catarina (UFSC), Florianópolis, Brazil 2 Department of Pharmacology, Center of Biological Sciences, Federal University of Santa Catarina (UFSC), Florianópolis 88049-900, Brazil 3 Research Group on Biology of Exercise, Department of Health Sciences, Federal University of Santa Catarina (UFSC), Araranguá, Brazil 4 CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal 5 Faculty of Medicine, University of Coimbra, 3005-504 Coimbra, Portugal Molecular Neurobiology https://doi.org/10.1007/s12035-018-1278-3