title: l-DOPA dosage is critically involved in dyskinesia via loss of synaptic depotentiation.
abstract: The emergence of levodopa (l-DOPA)-induced dyskinesia and motor fluctuations represents a major clinical problem in Parkinson's disease (PD). While it has been suggested that the daily dose of l-DOPA can play a critical role, the mechanisms linking l-DOPA dosage to the occurrence of motor complications have not yet been explored. Using an experimental model of PD we have recently demonstrated that long-term l-DOPA treatment leading to the induction of abnormal involuntary movements (AIMs) alters corticostriatal bidirectional synaptic plasticity. Dyskinetic animals, in fact, lack the ability to reverse previously induced long-term potentiation (LTP). This lack of depotentiation has been associated to a defect in erasing unessential motor information. Here chronic l-DOPA treatment was administered at two different doses to hemiparkinsonian rats, and electrophysiological recordings were subsequently performed from striatal spiny neurons. Both low and high doses of l-DOPA restored normal LTP, which was disrupted following dopamine (DA) denervation. By the end of the chronic treatment, however, while the low l-DOPA dose induced AIMs only in half of the rats, the high dose caused motor complications in all the treated animals. Interestingly, the dose-related expression of motor complications was associated with a lack of synaptic depotentiation. Our study provides further experimental evidence to support a direct correlation between the daily dosage of l-DOPA and the induction of motor complications and establishes a critical pathophysiological link between the lack of synaptic depotentiation and the expression of AIMs.
authors.affiliation: Laboratorio di Neurofisiologia, Fondazione Santa Lucia, IRCCS c/o CERC, Rome, Italy. b.picconi@hsantalucia.it
authors.forename: Barbara
authors.initials: B
authors.lastname: Picconi
authors.forename: Vincent
authors.initials: V
authors.lastname: Paillé
authors.forename: Veronica
authors.initials: V
authors.lastname: Ghiglieri
authors.forename: Vincenza
authors.initials: V
authors.lastname: Bagetta
authors.forename: Ilaria
authors.initials: I
authors.lastname: Barone
authors.forename: Hanna S
authors.initials: HS
authors.lastname: Lindgren
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bernardi
authors.forename: M
authors.initials: M
authors.lastname: Angela Cenci
authors.forename: Paolo
authors.initials: P
authors.lastname: Calabresi
mesh_terms: D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects*; D003342:Corpus Striatum / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D004409:Dyskinesia, Drug-Induced / Q000209:etiology* / Q000473:pathology*; D004558:Electric Stimulation; D066298:In Vitro Techniques; D007980:Levodopa / Q000009:adverse effects*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D036881:Long-Term Synaptic Depression / Q000187:drug effects; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000188:drug therapy / Q000209:etiology; D051381:Rats; D017208:Rats, Wistar; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D018663:Adrenergic Agents; D000978:Antiparkinson Agents; D007980:Levodopa; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase