Motor fluctuations in levodopa treated parkinsonian rats: relation to lesion extent and treatment duration.
The pathogenesis of the motor fluctuations that complicate levodopa treatment of most parkinsonian patients remains uncertain. To evaluate the contribution of the degree of dopamine neuron loss and the duration of levodopa exposure, rats whose nigrostriatal system had been previously lesioned unilaterally by 6-hydroxydopamine received twice daily levodopa (25 mg/kg) injections for three weeks. The magnitude of the rotational response to levodopa more than doubled during the first week of treatment (P < 0.01), but remained essentially constant thereafter. Rats with over 95 percent loss of dopaminergic neurons evidenced a progressive shortening in the duration of levodopa's motor effects (P < 0.01) as well as a failure of nearly 8 percent of levodopa injections to elicit any response after the first week of treatment. In contrast, response changes resembling those associated with end of dose deterioration and on-off fluctuations in parkinsonian patients did not occur in the less severely lesioned rats. These results suggest that the extent of a dopamine neuron loss must exceed a relatively high threshold before intermittent levodopa treatment produces changes favoring the rapid appearance of motor fluctuations of the wearing-off and on-off types.
Experimental Therapeutics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892.
S M
SM
Papa
T M
TM
Engber
A M
AM
Kask
T N
TN
Chase
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D003714:Denervation; D007150:Immunohistochemistry; D007980:Levodopa / Q000627:therapeutic use*; D008297:Male; D008474:Medial Forebrain Bundle / Q000502:physiology; D009068:Movement / Q000187:drug effects / Q000502:physiology*; D017072:Neostriatum / Q000473:pathology; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012399:Rotation; D013378:Substantia Nigra / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D007980:Levodopa; D016627:Oxidopamine; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase; D001058:Apomorphine