cp-94253 and Parkinson-Disease--Secondary

Parkinson's disease (PD) is characterized by a progressive degeneration of substantia nigra dopaminergic neurons projecting to the striatum. Restoration of dopamine transmission by L-DOPA relieves symptoms of PD but causes prominent side effects. There is a strong serotonin innervation of the striatum by serotonergic neurons that remains relatively preserved in PD. The study of this innervation has been largely neglected. Here, we demonstrate that chronic L-DOPA administration to 6-OHDA-lesioned rodents increases, via D1 receptors, the levels of the 5-HT1B receptor and its adaptor protein, p11, in dopamine-denervated striatonigral neurons. Using unilaterally 6-OHDA-lesioned p11 WT and KO mice, it was found that administration of a selective 5-HT1B receptor agonist, CP94253, inhibited L-DOPA-induced rotational behavior and abnormal involuntary movements in a p11-dependent manner. These data reveal an L-DOPA-induced negative-feedback mechanism, whereby the serotonin system may influence the symptomatology of Parkinsonism.

Topics: Animals; Autoradiography; Benzazepines; Corpus Striatum; Disease Models, Animal; Dopamine Antagonists; Immunohistochemistry; Levodopa; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Oxidopamine; Parkinson Disease, Secondary; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1B; RNA, Messenger; Serotonin Receptor Agonists