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.