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Key points: In newborn rats, L‐DOPA increases the occurrence of air‐stepping activity without affecting movement characteristics.L‐DOPA administration increases the spinal content of dopamine in a dose‐dependent manner.Injection of 5‐HTP increases the spinal serotonin content but does not trigger air‐stepping.5‐HTP counteracts the pro‐locomotor action of L‐DOPA.Less dopamine and serotonin are synthesized when L‐DOPA and 5‐HTP are administered as a cocktail. The catecholamine precursor, L‐3,4‐dihydroxyphenylalanine (L‐DOPA), is a well‐established pharmacological agent for promoting locomotor action in vertebrates, including triggering air‐stepping activities in the neonatal rat. Serotonin is also a well‐known neuromodulator of the rodent spinal locomotor networks. Here, using kinematic analysis, we compared locomotor‐related activities expressed by newborn rats in response to varying doses of L‐DOPA and the serotonin precursor 5‐hydroxytryptophan (5‐HTP) administered separately or in combination. L‐DOPA alone triggered episodes of air‐stepping in a dose‐dependent manner (25–100 mg/kg), notably determining the duration of locomotor episodes, but without affecting step cycle frequency or amplitude. In contrast, 5‐HTP (25–150 mg/kg) was ineffective in instigating air‐stepping, but altered episode durations of L‐DOPA‐induced air‐stepping, and decreased locomotor cycle frequency. High performance liquid chromatography revealed that L‐DOPA, which was undetectable in control conditions, accumulated in a dose‐dependent manner in the lumbar spinal cord 30 min after its administration. This was paralleled by an increase in dopamine levels, whereas the spinal content of noradrenaline and serotonin remained unaffected. In the same way, the spinal levels of serotonin increased in parallel with the dose of 5‐HTP without affecting the levels of dopamine and noradrenaline. When both precursors are administrated, they counteract each other for the production of serotonin and dopamine. Our data thus indicate for the first time that both L‐DOPA and 5‐HTP exert opposing neuromodulatory actions on air‐stepping behaviour in the developing rat, and we speculate that competition for the production of dopamine and serotonin occurs when they are administered as a cocktail. [ABSTRACT FROM AUTHOR]

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." [ABSTRACT FROM AUTHOR]