Side effect profile of 5‐ HT treatments for P arkinson's disease and L ‐ DOPA ‐induced dyskinesia in rats

Background and Purpose Treatment of P arkinson'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‐ HT 1 A 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 Approach S prague‐ D awley rats were given unilateral nigrostriatal dopamine lesions with 6‐hydroxydopamine. Each of the following three purportedly anti‐dyskinetic 5‐ HT compounds were administered 15 min before L ‐ DOPA : the full 5‐ HT 1 A agonist ±‐8‐hydroxy‐2‐dipropylaminotetralin (±8‐ OH ‐ DPAT ), the partial 5‐ HT 1 A 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 Results Each 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 Implications The results suggest that compounds that indirectly facilitate 5‐ HT 1 A receptor activation, such as citalopram, may be more effective therapeutics than direct 5‐ HT 1 A receptor agonists because they exhibit similar anti‐dyskinesia efficacy, while possessing a reduced side effect profile.