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.”

Control of locomotion relies on motor loops conveying modulatory signals between brainstem and spinal motor circuits. Here, we have investigated the steering control of the brainstem reticular formation over the spinal locomotor networks, using isolated brainstem-spinal cord preparations of male and female neonatal rats. First, we performed patch-clamp recordings of identified reticulospinal cells during episodes of fictive locomotion. This revealed that a spinal ascending phasic modulation of reticulospinal cell activity is already present at birth. Half of the cells exhibited tonic firing during locomotion while the other half emitted phasic discharges of action potentials phase-locked to ongoing activity. We next showed that mimicking the phasic activity of reticulospinal neurons by applying patterned electrical stimulation bilaterally at the ventral caudal medulla level, triggered fictive locomotion efficiently. Moreover, the brainstem stimuli-induced locomotor rhythm was entrained in a one to one coupling over a range of cycle periods (2-6 seconds). Additionally, we induced turning like motor outputs by either increasing or decreasing the relative duration of the stimulation trains on one side of the brainstem as compared to the other. The ability of the patterned descending command to control the locomotor output depended on the functional integrity of ventral reticulospinal pathways and the involvement of local spinal CPG circuitry. Altogether, this study provides a mechanism by which brainstem reticulospinal neurons relay steering and speed commands to the spinal locomotor networks. SIGNIFICANCE STATEMENT Locomotor function allows the survival of most animal species while sustaining the expression of fundamental behaviors. Locomotor activities adapt from moment to moment to behavioral and environmental changes. We show that the brainstem can control the spinal locomotor network outputs through phasic descending commands that alternate bilaterally. Manipulating the periodicity and/or the relative durations of the left and right descending commands at the brainstem level is efficient to set the locomotor speed and sustain directional changes.

L-DOPA triggers a dose-dependent increase in locomotor activity in newborn rats suspended in the air (air-stepping). Here, we report the effects of L-DOPA injection on the tissue level of monoamines and metabolites in different regions of the central nervous system (CNS) of postnatal day 5 pups. We also established correlations between some of our neurochemical measurements and basic locomotor parameters. L-DOPA (25–100 mg/kg) enhanced its tissue levels in the spinal cord, cortex, striatum, and brainstem regions. It induced a strong increase in the levels of the L-DOPA, dopamine, and their metabolites but had low effects on noradrenaline and serotonin across CNS regions. Of note, we also detected the tyramine derivative octopamine in the spinal cord. The inter-regional pattern of correlations between monoamine content showed an almost full metabolic connectivity for dopamine only when all L-DOPA conditions were pooled, and it revealed restricted connectivity for noradrenaline and serotonin in the spinal cord and the mesencephalic locomotor region. Locomotor parameters (quadrupedal locomotion and step numbers) correlated with the levels of L-DOPA and DA in restricted CNS regions at variance with noradrenaline and serotonin. Altogether, our data extend the idea that the neurochemical effect of L-DOPA is widespread and heterogeneous in the CNS, with prominent biochemical changes notably present in the spinal cord and M1 cortex, to the newborn rat.