Marie Boulain

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.

L-DOPA, the precursor of catecholamines, exerts a pro-locomotor action in several vertebrate species, including newborn rats. Here, we tested the hypothesis that decreasing the degradation of monoamines can promote the pro-locomotor action of a low, subthreshold dose of L-DOPA in five-day-old rats. The activity of the degrading pathways involving monoamine oxidases or catechol-O-methyltransferase was impaired by injecting nialamide or tolcapone, respectively. At this early post-natal stage, the capacity of the drugs to trigger locomotion was investigated by monitoring the air-stepping activity expressed by the animals suspended in a harness above the ground. We show that nialamide (100 mg/kg) or tolcapone (100 mg/kg), without effect on their own promotes maximal expression of air-stepping sequences in the presence of a sub-effective dose of L-DOPA (25 mg/kg). Tissue measurements of monoamines (dopamine, noradrenaline, serotonin and some of their metabolites) in the cervical and lumbar spinal cord confirmed the regional efficacy of each inhibitor toward their respective enzyme. Our experiments support the idea that the raise of monoamines boost L-DOPA’s locomotor action. Considering that both inhibitors differently altered the spinal monoamines levels in response to L-DOPA, our data also suggest that maximal locomotor response can be reached with different monoamines environment.

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.”