Parkinson's disease has long been associated with neurodegeneration of the dopaminergic neurons located in the substantia nigra. The metabolic precursor L-DOPA, administered exogenously to patients, has proven its superiority over other medications. Yet, its effectiveness is altered after long-term use by diverse motor and non-motor symptoms. Knowledge of its mechanism of action would be necessary to better apprehend the side effects, but do we really know where and how it works? The connexion between L-DOPA and the serotonergic system, after a sort of crusade lasting for more than 40 years, has been acknowledged recently. The purpose of this review, mainly based on preclinical data, is to present the pharmacological and biochemical evidence demonstrating that serotonergic neurons are mainly involved in the enhancement of dopamine transmission induced by L-DOPA. We are addressing thereafter the two main expectations coming from this mechanism that are fundamental and clinical. The fundamental part will focus on the conceptual framework imposed by such a mechanism, questioning notably the notion that the benefit of L-DOPA is associated with a restoration of dopamine levels in the caudate-putamen. The clinical part will discuss s...Continue Reading
Biotransformation of L-dopa in striatum and substantia nigra of rats with a unilateral, nigrostriatal lesion: a microdialysis study
Simultaneous microdialysis in striatum and substantia nigra suggests that the nigra is a major site of action of L-dihydroxyphenylalanine in the "hemiparkinsonian" rat
The metabolism of exogenous L-dopa in the brain: an immunohistochemical study of its conversion to dopamine in non-catecholaminergic cells of the rat brain
Comparison of effects of L-dopa, amphetamine and apomorphine on firing rate of rat dopaminergic neurones
Pharmacologic effects of L-dopa are not closely linked temporally to striatal dopamine concentration
Dopamine increase in the prefrontal cortex correlates with reversal of haloperidol-induced catalepsy in rats
L-DOPA is converted to dopamine in serotonergic fibers of the striatum of the rat: a double-labeling immunofluorescence study
Biotransformation of locally applied precursors of dopamine, serotonin and noradrenaline in striatum and hippocampus: a microdialysis study
Role of high-affinity dopamine uptake and impulse activity in the appearance of extracellular dopamine in striatum after administration of exogenous L-DOPA: studies in intact and 6-hydroxydopamine-treated rats
Role of serotonergic neurons in L-DOPA-derived extracellular dopamine in the striatum of 6-OHDA-lesioned rats
Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature
Transcription factors involved in the pathogenesis of L-DOPA-induced dyskinesia in a rat model of Parkinson's disease
Multicenter, open-label, trial of sarizotan in Parkinson disease patients with levodopa-induced dyskinesias (the SPLENDID Study)
Levodopa-induced changes in synaptic dopamine levels increase with progression of Parkinson's disease: implications for dyskinesias
Rasagiline as an adjunct to levodopa in patients with Parkinson's disease and motor fluctuations (LARGO, Lasting effect in Adjunct therapy with Rasagiline Given Once daily, study): a randomised, double-blind, parallel-group trial
L-DOPA-induced dyskinesia in adult rats with a unilateral 6-OHDA lesion of dopamine neurons is paralleled by increased c-fos gene expression in the subthalamic nucleus
In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primates, the selective 5-hydroxytryptamine 1a agonist (R)-(+)-8-OHDPAT inhibits levodopa-induced dyskinesia but only with\ increased motor disability
The nociceptin/orphanin FQ receptor antagonist J-113397 and L-DOPA additively attenuate experimental parkinsonism through overinhibition of the nigrothalamic pathway
Dopamine released from 5-HT terminals is the cause of L-DOPA-induced dyskinesia in parkinsonian rats
Inhibition of 5-HT neuron activity and induction of depressive-like behavior by high-frequency stimulation of the subthalamic nucleus.
Contribution of the striatum to the effects of 5-HT1A receptor stimulation in L-DOPA-treated hemiparkinsonian rats.
Local administration of sarizotan into the subthalamic nucleus attenuates levodopa-induced dyskinesias in 6-OHDA-lesioned rats.
The role of the dorsal raphe nucleus in the development, expression, and treatment of L-dopa-induced dyskinesia in hemiparkinsonian rats.
VGLUT3 (vesicular glutamate transporter type 3) contribution to the regulation of serotonergic transmission and anxiety.
Potential mechanisms underlying anxiety and depression in Parkinson's disease: consequences of l-DOPA treatment.
Presynaptic dopaminergic compartment determines the susceptibility to L-DOPA-induced dyskinesia in rats.
Multisite intracerebral microdialysis to study the mechanism of L-DOPA induced dopamine and serotonin release in the parkinsonian brain
Serotonergic modulation of the activity of mesencephalic dopaminergic systems: Therapeutic implications
Expanding the repertoire of L-DOPA's actions: A comprehensive review of its functional neurochemistry
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