title: L-DOPA and serotonergic neurons: functional implication and therapeutic perspectives in Parkinson's disease.
abstract: L-DOPA is the gold standard medication of Parkinson's disease, a neurological disorder consequent upon the degeneration of mesencephalic dopaminergic neurons. The therapeutic efficacy of L-DOPA has been related to its ability to restore dopamine (DA) extracellular levels in the Parkinsonian brain. The origin of the L-DOPA-induced rise in DA has been the object of numerous studies and controversies but the data collectively point to serotonergic (5-HT) neurons as being most significant in the release. Here, we review biochemical and behavioral evidence supporting serotonergic neurons as playing the main role in the actions of L-DOPA, considered from two points of view. The main aspect concerns the biochemical demonstration that 5-HT neurons are almost solely implicated in the release of DA induced by L-DOPA. The mechanism of action of L-DOPA inside 5-HT neurons will be thoroughly dissected on the basis of L-DOPA effects on extracellular versus tissue DA levels. The unique contribution of 5-HT neurons in mediating the release of newly synthesised DA from L-DOPA will be discussed in parallel with DA-dependent behaviors induced by L-DOPA. The other, and neglected, aspect concerns the possible deleterious impact of the presence of L-DOPA inside 5-HT neurons on 5-HT neuronal function. Overall, the fact that 5-HT neurons release the newly synthesised DA from L-DOPA in multiple brain regions beyond the striatum gives new insight into the large impact of L-DOPA in the Parkinsonian brain and strengthens therapeutic perspectives targeting the 5-HT system to reduce both motor and non-motor complications of L-DOPA medication.
authors: Université de Bordeaux, Unité Mixte de Recherche Centre National de la Recherche Scientifique 5293, 33076 Bordeaux cedex, France. sylvia.navailles@u-bordeaux2.fr
authors: Sylvia
authors: S
authors: Navailles
authors: Manolo
authors: M
authors: Carta
authors: Martin
authors: M
authors: Guthrie
authors: Philippe
authors: P
authors: De Deurwaerdère
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D004298:Dopamine / Q000378:metabolism; D006801:Humans; D007980:Levodopa / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism*; D059326:Serotonergic Neurons / Q000187:drug effects / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism
chemical_list: D000978:Antiparkinson Agents; D012701:Serotonin; D007980:Levodopa; D004298:Dopamine