title: Serotonergic nerve fibers in L-DOPA-derived dopamine release and dyskinesia.
abstract: The 5-HT (5-hydroxytryptamine) system has been assigned a key role in the development of 3,4-dihydroxyphenyl-l-alanine (l-DOPA)-induced dyskinesia, mainly due to 5-HT neuronal ability to decarboxylate l-DOPA into dopamine. Nevertheless, knowledge of l-DOPA-induced events that could lead to development of dyskinesias are limited and therefore the present work has evaluated (i) the role of the 5-HT system in l-DOPA-derived dopamine synthesis when dopamine neurons are present, (ii) l-DOPA-induced effects on striatal dopamine release and clearance, and on 5-HT nerve fiber density, and (iii) the behavioral outcome of altered 5-HT transmission in dyskinetic rats. Chronoamperometric recordings demonstrated attenuated striatal l-DOPA-derived dopamine release (∼30%) upon removal of 5-HT nerve fibers in intact animals. Interestingly, four weeks of daily l-DOPA treatment yielded similar-sized dopamine peak amplitudes in intact animals as found after a 5-HT-lesion. Moreover, chronic l-DOPA exposure attenuated striatal 5-HT nerve fiber density in the absence of dopamine nerve terminals. Furthermore, fluoxetine-induced altered 5-HT transmission blocked dyskinetic behavior via action on 5-HT1A receptors. Taken together, the results indicate a central role for the 5-HT system in l-DOPA-derived dopamine synthesis and in dyskinesia, and therefore potential l-DOPA-induced deterioration of 5-HT function might reduce l-DOPA efficacy as well as promote the upcoming of motor side effects.
authors.affiliation: Integrative Medical Biology, Umeå University, 901 87 Umeå, Sweden.
authors.forename: N
authors.initials: N
authors.lastname: Nevalainen
authors.affiliation: Integrative Medical Biology, Umeå University, 901 87 Umeå, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Af Bjerkén
authors.affiliation: Department of Anatomy, Neurobiology, and Neurology, University of Kentucky Medical Center, Lexington, KY, USA.
authors.forename: G A
authors.initials: GA
authors.lastname: Gerhardt
authors.affiliation: Integrative Medical Biology, Umeå University, 901 87 Umeå, Sweden. Electronic address: ingrid.stromberg@umu.se.
authors.forename: I
authors.initials: I
authors.lastname: Strömberg
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism*; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy; D005260:Female; D005473:Fluoxetine / Q000627:therapeutic use; D007980:Levodopa / Q000494:pharmacology*; D009412:Nerve Fibers / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D059326:Serotonergic Neurons / Q000187:drug effects* / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism
chemical_list: D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D005473:Fluoxetine; D007980:Levodopa; D004298:Dopamine
keywords: 5,7-DHT; 5,7-dihydroxytryptamine; 5-HT; 6-OHDA; 6-hydroxydopamine; AIM; ANOVA; LGE; LID; PBS; SERT; Serotonin; TH; WAY-100 635; abnormal involuntary movement; analysis of variance; dyskinesia; fluoxetine; in vivo chronoamperometry; l-DOPA; l-DOPA-induced dyskinesia; lateral ganglionic eminence; phosphate-buffered saline; serotonin transporter; tyrosine hydroxylase