Entacapone increases and prolongs the central effects of l-DOPA in the 6-hydroxydopamine-lesioned rat.
Long-term palliative treatment of Parkinson's disease (PD) with the dopamine precursor l-3,4-dihydroxyphenylalanine ( l-DOPA, levodopa) is compromised by the occurrence of motor complications, most notably motor fluctuations and involuntary movements, l-DOPA-induced dyskinesias. This study was aimed at investigating the effect of adding the catechol- O-methyltransferase (COMT) inhibitor entacapone to chronic treatment with l-DOPA/benserazide. It was hoped that the administration of entacapone would prolong and smooth the central effect of l-DOPA exposure and that this would result in a reduced risk of l-DOPA-induced dyskinesia induction by lowering the l-DOPA dose. The rotational response and striatal extracellular dopamine release were assessed in rats that had undergone a unilateral 6-hydroxydopamine-induced lesion of the nigro-striatal system. Previous studies have shown that repeated treatment with l-DOPA is accompanied by a marked enhancement in behavioural responses and has pharmacological characteristics similar to l-DOPA-induced dyskinesia. In the present study, we demonstrated that rats receiving entacapone in addition to 6.50 mg/kg of l-DOPA displayed significant enhancement of the developing contralateral turning response compared with rats treated with the same dose of l-DOPA only. However, when reducing the l-DOPA dose to 4.25 mg/kg the behavioural response was comparable to that seen in rats treated with the higher dose of l-DOPA only. Voltammetry analysis suggests that the increased behavioural response in entacapone-treated rats is the result of a much larger dopamine release. In addition, we found that entacapone treatment prolonged and smoothed the striatal dopamine levels following chronic l-DOPA/benserazide treatment. From a clinical point of view, this finding suggests that administration of a COMT inhibitor should allow the frequency of l-DOPA administration to decrease and to smooth the brain delivery of the l-DOPA, which in the end should facilitate a reduction in the risk of dyskinesia induction.
Gerlach
Manfred
M
Laboratory of Clinical Neurochemistry, Clinic for Child and Adolescent Psychiatry and Psychotherapy, University of Würzburg, Füchsleinstrasse 15, 97080 Würzburg, Germany. manfred.gerlach@mail.uni-wuerzburg.de
van den Buuse
Maarten
M
Blaha
Charles
C
Bremen
Dirk
D
Riederer
Peter
P
D000818:Animals; D002396:Catechols / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004357:Drug Synergism; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D009570:Nitriles; D016627:Oxidopamine / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley
D002396:Catechols; D009570:Nitriles; D007980:Levodopa; C071192:entacapone; D016627:Oxidopamine; D004298:Dopamine