Editor's Choice Article and Review
Volume 25, Issue 16, pages 2777-2784, 15 December 2010
Exercise elevates dopamine D2 receptor in a mouse model of Parkinson's disease: In vivo imaging with [18F]fallypride†
Marta G. Vučcković MSc1,2, Quanzheng Li PhD3, Beth Fisher PT, PhD4, Angelo Nacca PhD5, Richard M. Leahy PhD3, John P. Walsh PhD6, Jogesh Mukherjee PhD7, Celia Williams BSc2, Michael W. Jakowec PhD2,4, Giselle M. Petzinger MD2,4*
1 Neuroscience Graduate Program, University of Southern California, Los Angeles, California, USA
2 The George and Mary Lou Boone Center for Parkinson's Disease Research, Department of Neurology; University of Southern California, Los Angeles, California, USA
3 Viterbi School of Engineering, University of Southern California, Los Angeles, California, USA
4Philips-Fisher Center for Brain Repair and Rehabilitation, Division of Biokinesiology and Physical Therapy, University of Southern California, Los Angeles, California, USA
5 Department of Radiology, University of Southern California, Los Angeles, California, USA
6 Andrus Gerontology Center, University of Southern California, Los Angeles, California, USA
7 Preclinical Imaging Center, Department of Psychiatry and Human Behavior, UC Irvine, Irvine, California, USA
The purpose of the current study was to examine changes in dopamine D2 receptor (DA-D2R) expression within the basal ganglia of MPTP mice subjected to intensive treadmill exercise. Using Western immunoblotting analysis of synaptoneurosomes and in vivo positron emission tomography (PET) imaging employing the DA-D2R specific ligand [18F]fallypride, we found that high intensity treadmill exercise led to an increase in striatal DA-D2R expression that was most pronounced in MPTP compared to saline treated mice. Exercise-induced changes in the DA-D2R in the dopamine-depleted basal ganglia are consistent with the potential role of this receptor in modulating medium spiny neurons (MSNs) function and behavioral recovery. Importantly, findings from this study support the rationale for using PET imaging with [18F]fallypride to examine DA-D2R changes in individuals with Parkinson's Disease (PD) undergoing high-intensity treadmill training.
© 2010 Movement Disorder Society
Summary and review by Leo Verhagen, MD, PhD
Associate Professor of Neurological Sciences, Rush University Medical Center, Chicago
Exercise has been receiving increasing attention as a means by which patients with Parkinson's disease can improve their functioning. Bicycling, (tango) dancing, and tai-chi are just a few examples of physical exercise that have recently been featured in the media and touted to favorably effect parkinsonian symptoms. Most clinicians would agree that, in general, exercise is important to maintain one's health and overall condition. It therefore makes perfect sense to advocate exercise therapy for patients with PD so that they can better compensate for their impaired motor function.
The effect of exercise on motor function, however, may go beyond just that. Animal studies suggest that exercise regulates brain function to modify parkinsonian features (1-3) while there is some evidence that it also protects against neurological injury (4,5). Human studies in patients with PD also suggest a beneficial effect of exercise on motor control (2,6,7) but the optimal type of exercise remains unknown. Several studies comparing high intensity resistive exercise with less intense forms of exercise are currently ongoing. Even less clear has been the matter of how exercise would bring about changes in the nervous system that result in improved motor performance.
The study by Marta Vuckovic et al. in this issue of Movement Disorders addresses exactly that question. The authors offer compelling animal data to suggest that high intensity exercise leads to increased dopamine D2 receptor expression.
The authors studied mice in 4 treatment groups. Two groups were rendered parkinsonian with intraperitoneal MPTP. The other two received normal saline as control. One group of MPTP mice and one group of saline mice were submitted to strenuous treadmill exercise, whereas the other two groups were not. Treadmill exercise at incremental speeds was performed 5 times a week, for 6 weeks.
Behaviorally, both the saline and MPTP mice increased their running speed significantly. Initially MPTP mice were slower but after 5 weeks their speed was no different from that of the saline mice. Without treadmill training, no increase was seen in maximal running speed after 6 weeks. The authors went on to use 2 techniques to gain insight in a potential mechanism for the motor improvement. Using western immunoblot analysis of synaptoneurosomal preparations of dorsal striatum, they found that exercise increased D2 dopamine receptor protein expression in MPTP mice, but not in saline mice. MPTP lesioning itself (without exercise) did not increase D2 expression. D1 receptor expression was not altered in any group. As a second technique the authors used [18F]fallypride, a radioligand with high affinity for D2 and D3 receptors, which is not readily displaced by endogenous dopamine and therefore is assumed resistant to changes due to depletion of dopamine. They found that exercise significantly increased [18F]fallypride binding in MPTP mice, but not in saline-treated mice. Striatal dopamine levels in the MPTP + exercise group were no different from those in the MPTP without exercise group.
Based on the results of these two complimentary techniques, the authors conclude that intensive treadmill running facilitates neuroplasticity through increased expression of striatal dopamine D2 receptor expression.
These interesting findings certainly support the argument that exercise does more than just improve one's overall condition. It will be fascinating to see if the reported changes in [18F]fallypride binding, thought to represent increased dopamine D2 expression, can be replicated in patients with PD, who undergo high-intensity treadmill training.
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About Leo Verhagen
Leo Verhagen, MD, PhD, is a board-certified neurologist, an Associate Professor at Rush Medical College, and the Medical Director of the Neurosurgery Program for Movement Disorders, at Rush University Medical Center, Chicago, Illinois. He specializes in the medical and surgical management of patients with Parkinson's disease and other Movement Disorders such as Essential Tremor and Dystonia.