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: Karl Strecker, Michael Adamaszek, Sven Ohm, Florian Wegner, Jürgen Beck, Johannes Schwarz
• Journal: Journal of neural transmission (Vienna, Austria : 1996) (J Neural Transm (Vienna)) Vol. 119 Issue 11 Pg. 1351-9 (Nov 2012) ISSN: 1435-1463 [Electronic] Austria
• PMID: 22569849 (Publication Type: Journal Article)

Chemical References

• Benzimidazoles
• Quinolines
• RGS Proteins
• Serotonin Antagonists
• Serotonin Receptor Agonists
• regulator of g-protein signaling 9
• flibanserin
• Levodopa
• Buspirone
• quinelorane

Topics

• Animals
• Benzimidazoles (therapeutic use)
• Buspirone (administration & dosage)
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Drug Interactions
• Dyskinesia, Drug-Induced (drug therapy, etiology, genetics, physiopathology)
• Exploratory Behavior (drug effects)
• Female
• Levodopa (adverse effects)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Quinolines (adverse effects)
• RGS Proteins (deficiency)
• Serotonin Antagonists (therapeutic use)
• Serotonin Receptor Agonists (administration & dosage)