Reversal of levodopa-induced motor fluctuations in experimental parkinsonism by NMDA receptor blockade.
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.
Papa
S M
SM
Experimental Therapeutics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892, USA.
Boldry
R C
RC
Engber
T M
TM
Kask
A M
AM
Chase
T N
TN
D000818:Animals; D000978:Antiparkinson Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D001058:Apomorphine / Q000494:pharmacology; D001545:Benserazide / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D007267:Injections; D007276:Injections, Intraventricular; D007980:Levodopa / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008297:Male; D009068:Movement / Q000187:drug effects; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012399:Rotation; D013239:Stereotyped Behavior / Q000187:drug effects; D013378:Substantia Nigra
D000978:Antiparkinson Agents; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D007980:Levodopa; D016291:Dizocilpine Maleate; D001545:Benserazide; D016627:Oxidopamine; D001058:Apomorphine