Continuous Dopaminergic Stimulation in Parkinson’s Disease – What Have We Learned from Positron-emission Tomography? Neurodegenerative Disease Parkinson’s Disease

Oral levodopa remains the most effective symptomatic drug for Parkinson’s disease (PD); however, its long-term use is limited by the emergence of motor fluctuations and involuntary movements, particularly in young-onset patients. A growing number of preclinical and clinical studies suggest that non-physiological pulsatile stimulation of striatal dopamine (DA) receptors induced by the use of short-acting oral levodopa preparations, which produce swinging levels of synaptic DA, may contribute to the onset of motor fluctuations and dyskinesias. By contrast, more continuous and less pulsatile forms of dopaminergic stimulation delivered by longeracting oral DA agonists result in a more stable clinical response and delay the development of motor complications, while steady infusions of apomorphine and levodopa can abolish motor fluctuations and dyskinesias. Based on these observations, new levodopa formulations and alternative routes of administration for both levodopa and DA agonists have been introduced in the treatment of PD during the last decade, including slow-release preparations, addition of a catechol-O-methyltransferase (COMT) (entacapone or tolcapone) or monoamine oxidase B (MAOB) inhibitor (rasagaline), intravenous and enteral (duodenal) infusions of levodopa and transdermal administration and subcutaneous infusion of DA-receptor agonists. All of these strategies aim to optimise the clinical response by achieving stable and prolonged levels of synaptic DA. However, whether these strategies truly provide continuous dopaminergic stimulation has not yet been ascertained.