Evidence for a role of the 5-HT1B receptor and its adaptor protein, p11, in L-DOPA treatment of an animal model of Parkinsonism.
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.
Zhang
Xiaoqun
X
Section of Translational Neuropharmacology, Department of Physiology and Pharmacology, Karolinska Institute, 17177 Stockholm, Sweden.
Andren
Per E
PE
Greengard
Paul
P
Svenningsson
Per
P
D000818:Animals; D001345:Autoradiography; D001552:Benzazepines / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D018492:Dopamine Antagonists / Q000494:pharmacology; D007150:Immunohistochemistry; D007980:Levodopa / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016627:Oxidopamine / Q000633:toxicity; D010302:Parkinson Disease, Secondary / Q000188:drug therapy*; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D044302:Receptor, Serotonin, 5-HT1B / Q000235:genetics / Q000502:physiology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
D001552:Benzazepines; C097067:CP 94253; D018492:Dopamine Antagonists; D011725:Pyridines; D012333:RNA, Messenger; D044302:Receptor, Serotonin, 5-HT1B; D017366:Serotonin Receptor Agonists; D007980:Levodopa; D016627:Oxidopamine