stepholidine and Parkinsonian-Disorders

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 D(2) receptor antagonist haloperidol, but blunted by 5-HT(1A) receptor antagonist WAY100635. Furthermore, the mRNA level of 5-HT(1A) decreased significantly on 6-OHDA-lesioned striata, whereas chronic L-SPD treatment restored 5-HT(1A) receptor mRNA level on the lesioned striata. The present data demonstrated that L-SPD elicited antidyskinesia effects via both dopamine (D(2) receptor antagonistic activity) and nondopamine (5-HT(1A) agonistic activity) mechanisms.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Analysis of Variance; Animals; Antiparkinson Agents; Antipsychotic Agents; Benzazepines; Berberine; CHO Cells; Corpus Striatum; Cricetinae; Cricetulus; Disease Models, Animal; Dopamine Agents; Drug Administration Schedule; Drug Interactions; Dyskinesias; Gene Expression Regulation; Levodopa; Male; Oxidopamine; Parkinsonian Disorders; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1A; RNA, Messenger; Serotonin Receptor Agonists; Transfection; Tritium