l-Stepholidine reduced l-DOPA-induced dyskinesia in 6-OHDA-lesioned rat model of Parkinson's disease

l-3,4-Dihydroxyphenylalanine (l-DOPA)-induced dyskinesia (LID) remains a challenge in Parkinson's disease (PD) drug therapy. In the present study, we examined the effect of l-stepholidine (l-SPD), a known dual dopamine receptor agent, on LID in 6-hydroxydopamine (6-OHDA)-lesioned PD rat model. Daily administration of l-DOPA to PD rats for 22 days induced steady expression of LID, co-administration of l-SPD with l-DOPA significantly ameliorated LID without compromising the therapeutic potency of l-DOPA, indicating that l-SPD attenuated LID development. l-SPD alone elicited stable contralateral rotational behavior without inducing significant dyskinesia. Acute administration of l-SPD to rats with established LID produced significant relief of dyskinesia; this effect was mimicked by D2 receptor antagonist haloperidol, but blunted by 5-HT1A receptor antagonist WAY100635. Furthermore, the mRNA level of 5-HT1A decreased significantly on 6-OHDA-lesioned striata, whereas chronic l-SPD treatment restored 5-HT1A receptor mRNA level on the lesioned striata. The present data demonstrated that l-SPD elicited antidyskinesia effects via both dopamine (D2 receptor antagonistic activity) and nondopamine (5-HT1A agonistic activity) mechanisms.