L-DOPA in Parkinson’s Disease: Looking at the “False” Neurotransmitters and Their Meaning

Abstract

L-3,4-dihydroxyphenylalanine (L-DOPA) has been successfully used in the treatment of Parkinson’s disease (PD) for more than 50 years. It fulfilled the criteria to cross the blood–brain barrier and counteract the biochemical defect of dopamine (DA). It remarkably worked after some adjustments in line with the initial hypothesis, leaving a poor place to the plethora of mechanisms involving other neurotransmitters or mechanisms of action beyond newly synthesized DA itself. Yet, its mechanism of action is far from clear. It involves numerous distinct cell populations and does not mimic the mechanism of action of dopaminergic agonists. L-DOPA-derived DA is mainly released by serotonergic neurons as a false neurotransmitter, and serotonergic neurons are involved in L-DOPA-induced dyskinesia. The brain pattern and magnitude of DA extracellular levels together with this status of false neurotransmitters suggest that the striatal effects of DA via this mechanism would be minimal. Other metabolic products coming from newly formed DA or through the metabolism of L-DOPA itself could be involved. These compounds can be trace amines and derivatives. They could accumulate within the terminals of the remaining monoaminergic neurons. These “false neurotransmitters,” also known for some of them as inducing an “amphetamine-like” mechanism, could reduce the content of biogenic amines in terminals of monoaminergic neurons, thereby impairing the exocytotic process of monoamines including L-DOPA-induced DA extracellular outflow. The aim of this review is to present the mechanism of action of L-DOPA with a specific attention to “false neurotransmission.”

Chronic Administration of Fipronil Heterogeneously Alters the Neurochemistry of Monoaminergic Systems in the Rat Brain

“…They were not detected in some parts of the cortex (including M2 and OFC), the striatum (DMS, DLS, VMS, VLS, aCd), as well as the GPe. Even if the levels are reputedly low in these brain regions, the elution time of NA, usually close to the solvent front [ 36 ], was not sufficiently spaced in one of our chromatographic conditions, impairing a good determination of the electrochemical signal, corresponding to NA in these brain regions. Some examples of chromatograms obtained in our conditions are reported in Supplementary Figure S1 .…”

“…This is likely due to the complexity of the metabolism of monoamines, which involves several enzymes, transporters, and cell partners. It is interesting to note that the number of correlations between DA and HVA (three enzymatic steps and different cell populations) was lower compared to DOPAC versus DA (two enzymatic steps, different cell populations) or DOPAC versus HVA (one enzymatic step, different cell populations) [ 28 , 36 , 40 , 59 ]. Moreover, the metabolism of monoamines differs between brain regions [ 30 , 40 ].…”

The Noradrenergic System in Parkinson’s Disease

“…However, in one study NA levels were still excessive after noradrenergic neurons were destroyed (Ostock et al, 2018). It is likely that other electrochemically active compounds were confounding the chromatograms (Chagraoui et al, 2019). Other data indicate that L-DOPA either inhibits or does not alter NA release in the cortex (Dayan and Finberg, 2003;Pascucci et al, 2012).…”

Mass spectrometry imaging identifies abnormally elevated brain l -DOPA levels and extrastriatal monoaminergic dysregulation in l -DOPA–induced dyskinesia

“…Several lines of evidence suggest that LID is associated not only with striatal fluctuation in DA but also with widespread dysregulation of monoaminergic system homeostasis, involving both motor and nonmotor circuits within and outside the basal ganglia ( 9 , 10 ). Such changes may occur when l -DOPA is taken up by nondopaminergic neurons containing AADC and converted to DA, which may, in turn, affect the synaptic concentration and signaling of other neurotransmitters ( 11 ). Besides contributing to LID, such alteration may also be involved in l -DOPA–induced nonmotor fluctuations ( 4 ).…”