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.