title: Effect of selective serotonin reuptake inhibitors via 5-HT1A receptors on L-DOPA-induced rotational behavior in a hemiparkinsonian rat model.
abstract: L-Dihydroxyphenylalanine (L-DOPA) is considered the gold standard for the treatment of Parkinson's disease (PD). However, long-term administration of L-DOPA can induce abnormal side effects. On the other hand, selective serotonin reuptake inhibitors (SSRIs) including fluoxetine have gained tremendous popularity in the treatment of depression in PD. SSRIs are thought to influence motor function in PD via pharmacological modification of interactions between serotonergic and dopaminergic networks, which are complex and not yet fully understand. In this study, intranigral injection of 6-hydroxydopamine (6-OHDA) in rats caused a significant loss of tyrosine hydroxylase immunoreactivity in the striatum and substantia nigra. However, tryptophan hydroxylase immunoreactivity of the striatum and raphe nucleus was unaffected by 6-OHDA. Immunohistochemical analysis reveal that the serotonergic system was unaffected by the injection of 6-OHDA. We demonstrated also that pre-treatment with fluoxetine significantly suppressed L-DOPA-induced rotational behavior. Additionally, fluoxetine suppressed L-DOPA-induced ERK1/2 and histone H3 phosphorylation. These effects of fluoxetine were abolished by pre-treatment with WAY 100135, a 5-HT(1A) antagonist. These results suggest that fluoxetine may influence motor function in PD via pharmacological modification of interactions between serotonergic and dopaminergic neuronal networks.
authors.affiliation: Department of Neurobiology, Kyoto Pharmaceutical University, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Inden
authors.forename: Mari
authors.initials: M
authors.lastname: Abe
authors.forename: Hideaki
authors.initials: H
authors.lastname: Minamino
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Takata
authors.forename: Kanji
authors.initials: K
authors.lastname: Yoshimoto
authors.forename: Ikuo
authors.initials: I
authors.lastname: Tooyama
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Kitamura
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D005473:Fluoxetine / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D007980:Levodopa / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D016627:Oxidopamine / Q000494:pharmacology; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D059326:Serotonergic Neurons / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D005473:Fluoxetine; D006657:Histones; D007980:Levodopa; D016627:Oxidopamine; D010879:Piperazines; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D058829:Serotonin 5-HT1 Receptor Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; D014446:Tyrosine 3-Monooxygenase; C081293:WAY 100135