title: Chronic L-DOPA therapy alters central serotonergic function and L-DOPA-induced dopamine release in a region-dependent manner in a rat model of Parkinson's disease.
abstract: The therapeutic benefit of L-DOPA is commonly attributed to restoration of dopamine (DA) extracellular levels in the striatum of Parkinsonian patients. However, the loss of efficacy of L-DOPA after chronic use is paradoxically associated with a similar or enhanced striatal DA response. Release of L-DOPA-derived DA depends on the widespread serotonergic (5-HT) innervation in the brain. Chronic exposure of 5-HT neurons to L-DOPA could lead to aberrant neurochemical responses beyond the striatum. Using multi-site intracerebral microdialysis in a rat model of Parkinson's disease, we showed that chronic L-DOPA treatment at a therapeutic dose (12 mg/kg/day for 10 days) homogeneously reduced basal 5-HT release and metabolism. These effects were paralleled by a decrease in tissue content of 5-HT and its metabolite. Chronic L-DOPA treatment severely altered the brain pattern of 5-HT and DA release responses to L-DOPA (3-12 mg/kg) with an overall loss of efficacy of L-DOPA to increase DA release. Our data demonstrate for the first time in vivo that the impairment of 5-HT neuronal function induced by chronic L-DOPA alters in a region-dependent manner L-DOPA-induced DA release. Changes in neurochemical pattern of L-DOPA in the brain may favour the occurrence of both motor and non-motor side effects.
authors.affiliation: Université de Bordeaux, 33076 Bordeaux Cedex, France. sylvia.navailles@u-bordeaux2.fr
authors.forename: Sylvia
authors.initials: S
authors.lastname: Navailles
authors.forename: Bernard
authors.initials: B
authors.lastname: Bioulac
authors.forename: Christian
authors.initials: C
authors.lastname: Gross
authors.forename: Philippe
authors.initials: P
authors.lastname: De Deurwaerdère
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000633:toxicity; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D004334:Drug Administration Schedule; D007980:Levodopa / Q000633:toxicity*; D008297:Male; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism* / Q000502:physiology
chemical_list: D000978:Antiparkinson Agents; D012701:Serotonin; D007980:Levodopa; D004298:Dopamine