Pj. Blanchet et al., MODULATION OF LEVODOPA-INDUCED MOTOR RESPONSE COMPLICATIONS BY NMDA ANTAGONISTS IN PARKINSONS-DISEASE, Neuroscience and biobehavioral reviews, 21(4), 1997, pp. 447-453
The complex dopamine-glutamate interactions within the basal ganglia a
re disrupted by chronic nigrostriatal denervation and standard replace
ment therapy with levodopa. Acute N-methyl-D-aspartate (NMDA) receptor
blockade is able to overcome the changes in dopamine D-1- and D-2-dep
endent responses and the progressive shortening in the duration of res
ponse induced by long-term exposure to levodopa in 6-hydroxydopamine-l
esioned rats. Preliminary results further suggest that NMDA receptor b
lockade can counteract levodopa-induced dyskinesias in ethyl-4-phenyl-
1,2,3,6-tetrahydropyridine-lesioned non-human primates and parkinsonia
n patients without substantially altering the motor benefit derived fr
om levodopa. These results appear to be in accordance with our 2-deoxy
glucose studies in 6-hydroxydopamine-lesioned rats showing that NMDA r
eceptor blockade can attenuate many of the changes in synaptic activit
y induced by levodopa, particularly in the striatopallidal complex. Ta
ken together, our observations suggest that abnormal glutamate transmi
ssion or dysregulation of NMDA receptor-mediated mechanisms contribute
to levodopa-induced motor response complications. Additional preclini
cal and clinical experiments need to be completed with well tolerated
glutamate antagonists to determine the full potential of glutamate rec
eptor blockade as a long-term strategy against levodopa-related motor
response complications in Parkinson's disease. (C) 1997 Elsevier Scien
ce Ltd.