title: Striatal mRNA expression patterns underlying peak dose L-DOPA-induced dyskinesia in the 6-OHDA hemiparkinsonian rat.
abstract: L-DOPA is the primary pharmacological treatment for relief of the motor symptoms of Parkinson's disease (PD). With prolonged treatment (⩾5 years) the majority of patients will develop abnormal involuntary movements as a result of L-DOPA treatment, known as L-DOPA-induced dyskinesia. Understanding the underlying mechanisms of dyskinesia is a crucial step toward developing treatments for this debilitating side effect. We used the 6-hydroxydopamine (6-OHDA) rat model of PD treated with a three-week dosing regimen of L-DOPA plus the dopa decarboxylase inhibitor benserazide (4 mg/kg and 7.5 mg/kgs.c., respectively) to induce dyskinesia in 50% of individuals. We then used RNA-seq to investigate the differences in mRNA expression in the striatum of dyskinetic animals, non-dyskinetic animals, and untreated parkinsonian controls at the peak of dyskinesia expression, 60 min after L-DOPA administration. Overall, 255 genes were differentially expressed; with significant differences in mRNA expression observed between all three groups. In dyskinetic animals 129 genes were more highly expressed and 14 less highly expressed when compared with non-dyskinetic and untreated parkinsonian controls. In L-DOPA treated animals 42 genes were more highly expressed and 95 less highly expressed when compared with untreated parkinsonian controls. Gene set cluster analysis revealed an increase in expression of genes associated with the cytoskeleton and phosphoproteins in dyskinetic animals compared with non-dyskinetic animals, which is consistent with recent studies documenting an increase in synapses in dyskinetic animals. These genes may be potential targets for drugs to ameliorate L-DOPA-induced dyskinesia or as an adjunct treatment to prevent their occurrence.
authors.affiliation: Brain Health Research Centre and Brain Research NZ Centre of Research Excellence, University of Otago, New Zealand; Department of Anatomy, University of Otago, New Zealand. Electronic address: lisa.m.smith@otago.ac.nz.
authors.forename: L M
authors.initials: LM
authors.lastname: Smith
authors.affiliation: Brain Health Research Centre and Brain Research NZ Centre of Research Excellence, University of Otago, New Zealand; Department of Anatomy, University of Otago, New Zealand.
authors.forename: L C
authors.initials: LC
authors.lastname: Parr-Brownlie
authors.affiliation: Gravida, National Centre for Growth and Development and the Laboratory for Evolution and Development, University of Otago, New Zealand; Department of Biochemistry, University of Otago, New Zealand.
authors.forename: E J
authors.initials: EJ
authors.lastname: Duncan
authors.affiliation: Department of Biochemistry, University of Otago, New Zealand.
authors.forename: M A
authors.initials: MA
authors.lastname: Black
authors.affiliation: Department of Anatomy, University of Otago, New Zealand.
authors.forename: N J
authors.initials: NJ
authors.lastname: Gemmell
authors.affiliation: Gravida, National Centre for Growth and Development and the Laboratory for Evolution and Development, University of Otago, New Zealand; Department of Biochemistry, University of Otago, New Zealand.
authors.forename: P K
authors.initials: PK
authors.lastname: Dearden
authors.affiliation: Brain Health Research Centre and Brain Research NZ Centre of Research Excellence, University of Otago, New Zealand; Department of Anatomy, University of Otago, New Zealand.
authors.forename: J N J
authors.initials: JN
authors.lastname: Reynolds
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology / Q000633:toxicity*; D001545:Benserazide / Q000494:pharmacology / Q000633:toxicity*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D004338:Drug Combinations; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism* / Q000473:pathology; D007839:Functional Laterality; D015870:Gene Expression / Q000187:drug effects; D007980:Levodopa / Q000494:pharmacology / Q000633:toxicity*; D008297:Male; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism*; D011897:Random Allocation; D017208:Rats, Wistar; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D000978:Antiparkinson Agents; D004338:Drug Combinations; D012333:RNA, Messenger; C005177:benserazide, levodopa drug combination; D007980:Levodopa; D001545:Benserazide; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase
keywords: 6-OHDA; Parkinson’s disease; RNA-seq; dyskinesia; l-DOPA; striatum