Side effect profile of 5-HT treatments for Parkinson's disease and L-DOPA-induced dyskinesia in rats

Background and PurposeTreatment of Parkinson's disease (PD) with L-DOPA eventually causes abnormal involuntary movements known as dyskinesias in most patients. Dyskinesia can be reduced using compounds that act as direct or indirect agonists of the 5-HT1A receptor, but these drugs have been reported to worsen PD features and are known to produce 5-HT syndrome', symptoms of which include tremor, myoclonus, rigidity and hyper-reflexia. Experimental ApproachSprague-Dawley rats were given unilateral nigrostriatal dopamine lesions with 6-hydroxydopamine. Each of the following three purportedly anti-dyskinetic 5-HT compounds were administered 15min before L-DOPA: the full 5-HT1A agonist -8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT), the partial 5-HT1A agonist buspirone or the 5-HT transporter inhibitor citalopram. After these injections, animals were monitored for dyskinesia, 5-HT syndrome, motor activity and PD akinesia. Key ResultsEach 5-HT drug dose-dependently reduced dyskinesia by relatively equal amounts (+/- 8-OH-DPAT citalopram buspirone), but 5-HT syndrome was higher with +/- 8-OH-DPAT, lower with buspirone and not present with citalopram. Importantly, with or without L-DOPA, all three compounds provided an additional improvement of PD akinesia. All drugs tempered the locomotor response to L-DOPA suggesting dyskinesia reduction, but vertical rearing was reduced with 5-HT drugs, potentially reflecting features of 5-HT syndrome. Conclusions and ImplicationsThe results suggest that compounds that indirectly facilitate 5-HT1A receptor activation, such as citalopram, may be more effective therapeutics than direct 5-HT1A receptor agonists because they exhibit similar anti-dyskinesia efficacy, while possessing a reduced side effect profile.