title: The 5-HT1A-receptor agonist flibanserin reduces drug-induced dyskinesia in RGS9-deficient mice.
abstract: Drug-induced dyskinesia is a major complication of dopamine replacement therapy in advanced Parkinson's disease consisting of dystonia, chorea and athetosis. Agonists at 5-HT1A-receptors attenuate levodopa-induced motor complications in non-human primates. Mice with increased dopamine D2 receptor (DRD2) signalling due to the lack of expression of the regulator of G-protein signalling 9 (RGS9) also develop dyskinesia following levodopa treatment. We investigated whether the 5-HT1A-receptor agonist flibanserin compared with buspirone reduces motor abnormalities induced by levodopa or quinelorane, a selective dopamine D2-receptor agonist. Following dopamine depletion via reserpine, 40 mice (20 wild-type and 20 RGS9 knock-out) were treated with flibanserin or buspirone in combination with levodopa or quinelorane. Motor behaviour was analysed using open field analysis. RGS9 knock-out mice displayed significantly more drug-induced dystonia (p < 0.04; t test) than wild type. In quinelorane-treated wild-type mice flibanserin as well as buspirone significantly reduced dystonia (p < 0.05). In RGS9 knock-out animals again both reduced quinelorane-induced dystonia. However, flibanserin was significantly more effective (p = 0.003). Following reserpine pretreatment and administration of levodopa wild-type and RGS 9 knock-out mice showed mild to moderate dystonia. Surprisingly, 10 mg/kg buspirone increased dystonia in both animal groups, whereas it was decreased by 10 mg/kg flibanserin. However, compared with levodopa alone only the increase of dystonia by buspirone was significant (p < 0.04). Flibanserin showed promising antidyskinetic effects in a model of drug-induced dyskinesia. Our data underline the possible benefit of 5-HT1A agonists in drug-induced dyskinesia.
authors.affiliation: NRZ, Neurological Rehabilitation Center, University of Leipzig, Muldentalweg 1, 04828 Bennewitz, Germany. KarlStrecker@gmx.de
authors.forename: Karl
authors.initials: K
authors.lastname: Strecker
authors.forename: Michael
authors.initials: M
authors.lastname: Adamaszek
authors.forename: Sven
authors.initials: S
authors.lastname: Ohm
authors.forename: Florian
authors.initials: F
authors.lastname: Wegner
authors.forename: Jürgen
authors.initials: J
authors.lastname: Beck
authors.forename: Johannes
authors.initials: J
authors.lastname: Schwarz
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000627:therapeutic use*; D002065:Buspirone / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D007980:Levodopa / Q000009:adverse effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011804:Quinolines / Q000009:adverse effects; D020710:RGS Proteins / Q000172:deficiency*; D012702:Serotonin Antagonists / Q000627:therapeutic use*; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage
chemical_list: D001562:Benzimidazoles; D011804:Quinolines; D020710:RGS Proteins; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C116925:regulator of g-protein signaling 9; C098107:flibanserin; D007980:Levodopa; D002065:Buspirone; C047726:quinelorane