title: 5-Hydroxy-tryptophan for the treatment of L-DOPA-induced dyskinesia in the rat Parkinson's disease model.
abstract: The serotonin system has recently emerged as an important player in the appearance of L-DOPA-induced dyskinesia (LID) in experimental models of Parkinson's disease, as it provides an unregulated source of L-DOPA-derived dopamine release in the dopamine-depleted striatum. Accordingly, toxin lesion or pharmacological silencing of serotonin neurons suppressed LID in the rat and monkey models of Parkinson's disease. However, 5-HT1 receptor agonists were also found to partially reduce the therapeutic effect of L-DOPA. In this study, we evaluated whether enhancement of the serotonin tone induced by the administration of the serotonin precursor 5-hydroxy-tryptophan (5-HTP) could affect induction and expression of LID, as well as the therapeutic effect of L-DOPA, in 6-OHDA-lesioned rats. Drug naïve and L-DOPA-primed 6-OHDA-lesioned rats were chronically treated with a daily injection of L-DOPA (6 mg/kg plus benserazide, s.c.) alone, or in combination with 5-HTP (24-48 mg/kg, i.p.). The abnormal involuntary movements (AIMs) test, as well as the stepping and the motor activity tests, were performed during the chronic treatments. Results showed that 5-HTP reduced the appearance of LID of about 50% at both tested doses. A partial reduction of the therapeutic effect of L-DOPA was seen with the higher but not with the lower dose of 5-HTP. 5-HTP 24 mg/kg was also able to reduce the expression of dyskinesia in L-DOPA-primed dyskinetic rats, to a similar extent than in L-DOPA-primed rats. Importantly, the antidyskinetic effect of 5-HTP 24 mg/kg does not appear to be due to a competition with L-DOPA for crossing the blood-brain barrier; in fact, similar L-DOPA striatal levels were found in L-DOPA only and L-DOPA plus 5-HTP 24 mg/kg treated animals. These data further confirm the involvement of the serotonin system in the appearance of LID, and suggest that 5-HTP may be useful to counteract the appearance of dyskinesia in Parkinson's disease patients.
authors.affiliation: Department of Biomedical Sciences, Cagliari University, Cagliari, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Tronci
authors.forename: Carlo
authors.initials: C
authors.lastname: Lisci
authors.forename: Roberto
authors.initials: R
authors.lastname: Stancampiano
authors.forename: Camino
authors.initials: C
authors.lastname: Fidalgo
authors.forename: Maria
authors.initials: M
authors.lastname: Collu
authors.forename: Paola
authors.initials: P
authors.lastname: Devoto
authors.forename: Manolo
authors.initials: M
authors.lastname: Carta
mesh_terms: D006916:5-Hydroxytryptophan / Q000008:administration & dosage / Q000627:therapeutic use*; D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D002421:Caudate Nucleus / Q000737:chemistry; D004195:Disease Models, Animal; D004298:Dopamine / Q000032:analysis; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy*; D005260:Female; D007980:Levodopa / Q000032:analysis / Q000633:toxicity*; D009043:Motor Activity / Q000187:drug effects; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000032:analysis
chemical_list: D018663:Adrenergic Agents; D012701:Serotonin; D007980:Levodopa; D016627:Oxidopamine; D006916:5-Hydroxytryptophan; D004298:Dopamine
keywords: 5-HTP; 5-hydroxy-tryptophan; 6-OHDA; 6-hydroxy-dopamine; AIMs; DA; Dopamine; Dyskinesia; LID; PD; Parkinson's disease; SSRIs; Serotonin; TH; abnormal involuntary movements; dopamine; l-DOPA; l-DOPA-induced dyskinesia; serotonin reuptake inhibitors; tyrosine hydroxylase