title: Imaging DA release in a rat model of L-DOPA-induced dyskinesias: a longitudinal in vivo PET investigation of the antidyskinetic effect of MDMA.
abstract: In the context of Parkinson's disease, motor symptoms result from the degeneration of nigrostriatal neurons. Dopamine (DA) replacement using l-3,4-dihydroxyphenylalanine (L-DOPA) has been the treatment of choice in the early stages of the disease. However, with disease progression, patients suffer from motor complications, which have been suggested to arise from DA released from serotonergic terminals according to the false neurotransmitter hypothesis. The synthetic amphetamine derivative (±) 3,4-methylenedioxymethamphetamine (MDMA) has been shown to significantly inhibit dyskinesia in humans and in animal models of PD. In this study, we examined the effect of MDMA on L-DOPA-induced DA release by using [(11)C]raclopride kinetic modeling to assess alterations in DA neurotransmission in a rat model of L-DOPA-induced dyskinesia (LID) in a longitudinal in vivo PET study. Rats were submitted to 6-OHDA lesions, and the lesions were confirmed to be sufficiently severe based on the performance during stepping tests and [(11)C]methylphenidate PET scans. The rats underwent two [(11)C]raclopride PET sessions before (baseline) and after two weeks of chronic L-DOPA treatment (priming). L-DOPA priming led to strong abnormal involuntary movements (AIMs). In group 1, L-DOPA priming reduced L-DOPA-induced DA release in the lesioned striatum with no effect on the healthy side, while the concomitant administration of L-DOPA and MDMA (group 2) increased the DA levels in the lesioned and healthy striatum. In addition, behavioral analysis, which was performed two weeks after the second PET session, confirmed the antidyskinetic effect of MDMA. Our data show that L-DOPA-induced DA release is attenuated in the Parkinsonian striatum after chronic L-DOPA pretreatment and that the antidyskinetic mechanism of MDMA does not depend primarily on dopaminergic neurotransmission.
authors: Neuropharmacology, Eberhard Karls University Tuebingen, Germany. nadine.lettfuss@uni-tuebingen.de
authors: Nadine Y
authors: NY
authors: Lettfuss
authors: Kristina
authors: K
authors: Fischer
authors: Vesna
authors: V
authors: Sossi
authors: Bernd J
authors: BJ
authors: Pichler
authors: Andreas
authors: A
authors: von Ameln-Mayerhofer
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000627:therapeutic use; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D004409:Dyskinesia, Drug-Induced / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000517:prevention & control*; D007980:Levodopa; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000627:therapeutic use*; D049268:Positron-Emission Tomography / Q000379:methods*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D018759:Adrenergic Uptake Inhibitors; D007980:Levodopa; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D004298:Dopamine