Cholinergic and dopaminergic mechanisms in Parkinson's disease after long-term L-DOPA administration

A study of parkinsonian patients suffering from ON-OFF phenomena, who had been on long-term treatment with L-DOPA, to the parenteral administration of apomorphine and physostigmine is reported. All patients, whether of the end-dose failure type or of the randomly occurring variety, when given apomorphine in an OFF phase, showed prompt reversal to an ON phase. Physostigmine given during an ON phase produced the opposite effect with induction of parkinsonian symptoms. These findings are interpreted as indicating that the dopaminergic receptors are available for stimulation during the OFF phase but are not receiving sufficient neurotransmitter, that is, dopamine, to stimulate their activity. The response to physostigmine is indicative of a return of cholinergic supersensitivity after long-term L-DOPA administration, the mechanisms by which this may occur are discussed. Based on these findings, therapeutic strategies are suggested that may overcome this major limitation of the use of L-DOPA in the treatment of parkinsonism.