Effects of voluntary exercise and NMDA receptor subunit selective antagonists on levodopa-induced motor response complications in hemiparkinsonian rats

Parkinson's disease (PD) is a neurodegenerative disorder characterized by akinesia, rigidity, and tremors at rest. At present, the most commonly used drug to treat PD is levodopa, which restore the neurotransmitter dopamine. Initially, treatment with levodopa confers substantial clinical benefit. Within a few years, however, nonphysiological stimulation of striatal dopamine receptors via this drug leads to the development of disabling motor response complications, the most prominent of which are called motor response fluctuations and dyskinesias. In the present study, two distinct novel strategies for treating these motor response complications---subunit-selective NMDA antagonists and voluntary exercise---were evaluated in the 6-OHDA rat model of PD. Sixty-one hemi-parkinsonian adult male rats were treated with levodopa twice daily for three weeks together with either NVP-AAM077 (NR2A antagonist), NVP-AAM077 plus CP-101,606 (NR2B antagonist), or PBS (control). In addition, an equal number of animals in each drug treatment group were given the opportunity to exercise on a running wheel. Animals were tested for behavioral deficit to evaluate the prophylactic as well as palliative effects of exercise alone and in combination with NMDA antagonists for their ability to modify forelimb akinesia, motor fluctuations, and dyskinesia, respectively. The results showed that NVP-AAM077 attenuated the levodopa-induced calcium dysregulaion in striatal spiny neurons, and prevented the development of shortening motor response and forelimb movement deficits caused by chronic levodopa treatment. Simultaneous administration of subthreshold doses of NVP-AAM077 and CP-101,606 ameliorated the wearing-off response and the forelimb movement deficits produced by chronic levodopa therapy. In hemiparkinsonian rats allowed to exercise, voluntary exercise reversed the dyskinesia and forelimb deficits and delayed the appearance of the shortened motor response to levodopa challenge produced by three weeks of twice daily levodopa treatment. Exercise therapy when combined with NMDA receptor blockade acted to provide a substantially greater delaying effect in the onset of response alterations induced by levodopa than an inhibition of either of these therapies alone. These results suggest that mechanisms mediated by glutamate receptors and exercise make independent contributions to the pathogenesis of these motor response changes suggest novel approaches to more effective and safer therapy of PD.