Serotonin 1A receptor agonists have attracted much interest recently as potential therapeutic agents for
levodopa-induced motor complications, such as
dyskinesia and motor fluctuations. The effects of
piclozotan (
SUN N4057) on a rat model of advanced
Parkinson's disease were investigated. Parkinsonian rats, unilaterally 6-hydroxydopamine-lesioned rats, were administered
levodopa for 8 to 9 weeks. Based on the results of rotational behavior and forelimb
hyperkinesia in Week 5, the rats were allocated to three treatment groups (saline and two dosing rates of
piclozotan set at 0.018 and 0.036 mg/kg/h).
Piclozotan was administered via continuous
subcutaneous infusion using an osmotic pump for 3 to 4 weeks. At Week 7 of repeated
levodopa dosing, the effects of
piclozotan on
levodopa-induced behavior were evaluated. In addition, extracellular levels of
levodopa-derived
dopamine in the striatum were measured using microdialysis in Weeks 8 to 9 after completion of the respective behavioral studies. Chronic treatment with
levodopa-induced forelimb
hyperkinesia and shortened the duration of rotational behavior.
Piclozotan (0.018 and 0.036 mg/kg/h, plasma concentrations 5.3±0.7 and 14.3±2.9 ng/ml) reduced
levodopa-induced forelimb
hyperkinesia by 55% and 69%, respectively, at 1h relative to the control.
Piclozotan (0.036 mg/kg/h) significantly lengthened the duration of rotational behavior by 26% versus the control and attenuated the increase in striatal
levodopa-derived extracellular
dopamine levels. These findings suggest that
piclozotan, a
serotonin 1A agonist, can improve motor complications in patients with advanced
Parkinson's disease.