Serotonin 5-HT1A agonist improves motor complications in rodent and primate parkinsonian models

Background: Serotoninergic transmission in the basal ganglia is known to influence dopaminergic mechanisms and motor function. Objective: To evaluate the possibility that serotoninergic 5-HT1A autoreceptors (by regulating the release of serotonin as well as dopamine formed from exogenous levodopa) affect the response alterations complicating levodopa treatment of PD. Methods: The 5-HT1A receptor agonist sarizotan (EMD128130) was systemically administered alone and together with levodopa to parkinsonian rats and nonhuman primates. Results: In 6-hydroxydopamine-lesioned rats, sarizotan (2.5 mg/kg PO) had no effect on the acute rotational response to levodopa but did attenuate the shortening in motor response duration induced by chronic levodopa treatment. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned monkeys, sarizotan (2 mg/kg PO) alone had no effect on parkinsonian severity or on the antiparkinsonian response to levodopa. In contrast, the same dose of sarizotan reduced levodopa-induced choreiform dyskinesias by 91 +/- 5.9%. In both species, the motoric effects of sarizotan were blocked by the selective 5-HT1A antagonist WAY100635 (0.1 mg/kg SC), indicating that the observed sarizotan responses were probably mediated at the 5-HT1A autoreceptor. Conclusion: Pharmaceuticals acting to stimulate 5-HT1A receptors could prove useful in the treatment of the motor response complications in parkinsonian patients.