Genome-wide microarray analysis identifies a potential role for striatal retrograde endocannabinoid signaling in the pathogenesis of experimental l-DOPA-induced dyskinesia

• Published in: Synapse (New York, N.Y.) Vol. 68; no. 8; pp. 332 - 343
• Main Authors: Wang, Yong, Zhang, Qiao Jun, Wang, Hui Sheng, Wang, Tao, Liu, Jian
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.08.2014; Wiley Subscription Services, Inc
• Subjects: Adrenergic Agents - toxicity; Animals; Antiparkinson Agents - adverse effects; Corpus Striatum - drug effects; Corpus Striatum - physiopathology; dyskinesia; Dyskinesia, Drug-Induced - physiopathology; endocannabinoid; Endocannabinoids - metabolism; Gene Expression - drug effects; Gene Ontology; l-DOPA; Levodopa - adverse effects; Male; microarray; Microarray Analysis; Motor Activity - drug effects; Motor Activity - physiology; Oxidopamine - toxicity; Parkinson's disease; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction - drug effects; l-DOPA; endocannabinoid; microarray; Parkinson's disease; dyskinesia
• ISSN: 0887-4476; 1098-2396; 1098-2396
• DOI: 10.1002/syn.21740

ABSTRACT l‐3,4‐Dihydroxyphenylalanine (l‐DOPA) is the most widely used drug for the treatment of Parkinson's disease. Unfortunately, chronic administration of this dopamine precursor causes l‐DOPA‐induced dyskinesia (LID), which is a debilitating complication whose pathogenesis remains unclear. In this study, we compared gene expression profiles of sensorimotor striatum tissue derived from LID and non‐LID 6‐hydroxydopamine‐lesioned rats treated with l‐DOPA. Total RNA was amplified, transcribed and hybridized to Agilent Whole Rat Genome Oligo Microarray chips. Quantitative real‐time reverse transcription PCR was conducted to validate the microarray data. We detected 382 upregulated genes and 115 downregulated genes in LID rats when compared with that of non‐LID subjects with Significance Analysis for Microarrays software. The differentially expressed genes were mainly associated with postsynaptic cell membranes, synapses, and neurotransmitter receptors. Gene Set Analysis (GSA) software was used to identify differentially expressed gene ontology (GO) categories and pathways. The GSA found that “long‐term depression” and “retrograde endocannabinoid signaling” pathways were downregulated, whereas a set of lipid metabolism‐related GO categories and pathways were upregulated in LID rats compared with non‐LID controls. Our study provides further experimental evidence to support the direct correlation between abnormal striatal synaptic plasticity and the induction of LID, and it suggests that the dysfunction of the retrograde endocannabinoid signaling system, a lipid‐based neuromodulatory system, and the relevant alteration of the related lipid metabolism processes might play an important role in the pathogenesis of LID. Synapse 68:332–343, 2014. © 2014 Wiley Periodicals, Inc. What's new? The authors compared gene expression profiles of sensorimotor striatum tissue derived from rats with L‐3,4‐dihydroxyphenylalanine (L‐DOPA)‐induced dyskinesia (LID) and non‐LID 6‐hydroxydopamine‐lesioned rats treated with L‐DOPA. The results showed that abnormal striatal synaptic plasticity and the dysfunction of striatal retrograde endocannabinoid signaling might play an important role in the pathogenesis of LID.