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

• Published in: Brain research 1995-12, Vol.701 (1), p.13-18
• Main Authors: Papa, Stella M., Boldry, Robert C., Engber, Thomas M., Kask, Anne M., Chase, Thomas N.
• Format: Article
• Language: English
• Subjects: 6-Hydroxydopaminc lesion; Animals; Antiparkinson Agents - antagonists & inhibitors; Antiparkinson Agents - pharmacology; Apomorphine - pharmacology; Basal ganglia; Benserazide - pharmacology; Biological and medical sciences; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dizocilpine Maleate - administration & dosage; Dizocilpine Maleate - pharmacology; Dopamine; Excitatory Amino Acid Antagonists - administration & dosage; Excitatory Amino Acid Antagonists - pharmacology; Glutamate antagonist; Injections; Injections, Intraventricular; Levodopa - antagonists & inhibitors; Levodopa - pharmacology; Male; Medical sciences; MK-801; Motor function; Movement - drug effects; N-Methyl- d-aspartate; Neurology; On-off phenomenon; Oxidopamine; Parkinson Disease, Secondary - physiopathology; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Rotation; Stereotyped Behavior - drug effects; Substantia Nigra
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/0006-8993(95)00924-3

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.