Reversal of levodopa-induced motor fluctuations in experimental parkinsonism by NMDA receptor blockade

Reversal of levodopa-induced motor fluctuations in experimental parkinsonism by NMDA receptor... Dopaminoceptive system alterations in the basal ganglia have been implicated in the pathogenesis of wearing-off fluctuations that complicate levodopa therapy of Parkinson's disease. To evaluate the contribution of glutamatergic mechanisms to the associated changes in striatal efferent pathway function, we examined the ability of N -methyl- d -aspartate (NMDA) receptor blockade to modify the motor response changes produced by chronic levodopa administration to hemiparkinsonian rats. Unilaterally 6-hydroxydopamine lesioned rats, given levodopa/benserazide (25/6.25 mg/kg) twice daily for 3 weeks, developed a progressive shortening in the duration of their motor response to levodopa similar to that occurring in parkinsonian patients with wearing-off phenomenon. The acute systemic administration of MK-801 (0.1 mg/kg) to these animals completely reversed the decrease in turning duration ( P < 0.01). Intrastriatal injection of the NMDA antagonist was even more effective in prolonging the levodopa response ( P < 0.01), while intranigrally injected MK-801 produced no statistically significant change in the duration of levodopa-induced rotation. Rotational intensity was unaffected by all routes of MK-801 administration. These results suggest that drugs capable of blocking NMDA receptors, especially in striatum, may help ameliorate motor fluctuations in patients with advanced Parkinson's disease. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Brain Research Elsevier

Reversal of levodopa-induced motor fluctuations in experimental parkinsonism by NMDA receptor blockade

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Publisher
Elsevier
Copyright
Copyright © 1995 Elsevier Science B.V. All rights reserved
ISSN
0006-8993
D.O.I.
10.1016/0006-8993(95)00924-3
Publisher site
See Article on Publisher Site

Abstract

Dopaminoceptive system alterations in the basal ganglia have been implicated in the pathogenesis of wearing-off fluctuations that complicate levodopa therapy of Parkinson's disease. To evaluate the contribution of glutamatergic mechanisms to the associated changes in striatal efferent pathway function, we examined the ability of N -methyl- d -aspartate (NMDA) receptor blockade to modify the motor response changes produced by chronic levodopa administration to hemiparkinsonian rats. Unilaterally 6-hydroxydopamine lesioned rats, given levodopa/benserazide (25/6.25 mg/kg) twice daily for 3 weeks, developed a progressive shortening in the duration of their motor response to levodopa similar to that occurring in parkinsonian patients with wearing-off phenomenon. The acute systemic administration of MK-801 (0.1 mg/kg) to these animals completely reversed the decrease in turning duration ( P < 0.01). Intrastriatal injection of the NMDA antagonist was even more effective in prolonging the levodopa response ( P < 0.01), while intranigrally injected MK-801 produced no statistically significant change in the duration of levodopa-induced rotation. Rotational intensity was unaffected by all routes of MK-801 administration. These results suggest that drugs capable of blocking NMDA receptors, especially in striatum, may help ameliorate motor fluctuations in patients with advanced Parkinson's disease.

Journal

Brain ResearchElsevier

Published: Dec 1, 1995

References

  • The functional anatomy of basal ganglia disorders
    Albin, R.L.; Young, A.B.; Penney, J.B.
  • Wearing-off fluctuations in Parkinson's disease: contribution of postsynaptic mechanisms
    Bravi, D.; Mouradian, M.M.; Roberts, J.W.; Chase, T.N.
  • Antiparkinsonian effects of remacemide hydrochloride, a glutamate antagonist, in rodent and primate models of Parkinson's disease
    Greenamyre, J.T.; Eller, R.V.; Zhang, Z.; Ovadia, A.; Kurlan, R.; Gash, D.M.
  • Cloning of the genes for excitatory amino acids receptors
    Henneberry, R.C.
  • NMDA antagonists potentiate antiparkinsonian actions of L-Dopa in monoamine-depleted rats
    Klockgether, T.; Turski, L.
  • Toward an understanding of the role of glutamate in experimental parkinsonism: agonist-sensitive sites in the basal ganglia
    Klockgether, T.; Turski, L.
  • Dystonia induced by combined treatment with L-Dopa and MK-801 in parkinsonian monkeys
    Rupniak, N.M.J.; Boyce, S.; Steventon, M.J.; Iversen, S.D.; Marsden, C.D.

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