Experimental Dopamine Reuptake Inhibitors in Parkinson's Disease: A Review of the Evidence.

Parkinson's disease (PD) is the second most chronic neurodegenerative disorder worldwide. Deficit of monoamines, particularly dopamine, causes an individually varying compilation of motor and non-motor features. Constraint of presynaptic uptake extends monoamine stay in the synaptic cleft. This review discusses possible benefits of dopamine reuptake inhibition for the treatment of PD. Translation of this pharmacologic principle into positive clinical study results failed to date. Past clinical trial designs did not consider a mandatory, concomitant stable inhibition of glial monoamine turnover, i.e. with monoamine oxidase B inhibitors. These studies focused on improvement of motor behavior and levodopa associated motor complications, which are fluctuations of motor and non-motor behavior. Future clinical investigations in early, levodopa- and dopamine agonist naïve patients shall also aim on alleviation of non-motor symptoms, like fatigue, apathy or cognitive slowing. Oral levodopa/dopa decarboxylase inhibitor application is inevitably necessary with advance of PD. Monoamine reuptake (MRT) inhibition improves the efficacy of levodopa, the blood brain barrier crossing metabolic precursor of dopamine. The pulsatile brain delivery pattern of orally administered levodopa containing formulations results in synaptic dopamine variability. Ups and downs of dopamine counteract the physiologic principle of continuous neurotransmission, particularly in nigrostriatal, respectively mesocorticolimbic pathways, both of which regulate motor respectively non-motor behavior. Thus synaptic dopamine pulsatility overwhelms the existing buffering capacity. Onset of motor and non-motor complications occurs. Future MRT inhibitor studies shall focus on a stabilizing and preventive effect on levodopa related fluctuations of motor and non-motor behavior. Their long-term study designs in advanced levodopa treated patients shall allow a cautious adaptation of oral l-dopa therapy combined with a mandatory inhibition of glial monoamine turnover. Then the evidence for a preventive and beneficial, symptomatic effect of MRT inhibition on motor and non-motor complications will become more likely.