title: Methamphetamine-induced dopamine-independent alterations in striatal gene expression in the 6-hydroxydopamine hemiparkinsonian rats.
abstract: Unilateral injections of 6-hydroxydopamine into the medial forebrain bundle are used extensively as a model of Parkinson's disease. The present experiments sought to identify genes that were affected in the dopamine (DA)-denervated striatum after 6-hydroxydopamine-induced destruction of the nigrostriatal dopaminergic pathway in the rat. We also examined whether a single injection of methamphetamine (METH) (2.5 mg/kg) known to cause changes in gene expression in the normally DA-innervated striatum could still influence striatal gene expression in the absence of DA. Unilateral injections of 6-hydroxydopamine into the medial forebrain bundle resulted in METH-induced rotational behaviors ipsilateral to the lesioned side and total striatal DA depletion on the lesioned side. This injection also caused decrease in striatal serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels. DA depletion was associated with increases in 5-HIAA/5-HT ratios that were potentiated by the METH injection. Microarray analyses revealed changes (±1.7-fold, p<0.025) in the expression of 67 genes on the lesioned side in comparison to the intact side of the saline-treated hemiparkinsonian animals. These include follistatin, neuromedin U, and tachykinin 2 which were up-regulated. METH administration caused increases in the expression of c-fos, Egr1, and Nor-1 on the intact side. On the DA-depleted side, METH administration also increased the expression of 61 genes including Pdgf-d and Cox-2. There were METH-induced changes in 16 genes that were common in the DA-innervated and DA-depleted sides. These include c-fos and Nor-1 which show greater changes on the normal DA side. Thus, the present study documents, for the first time, that METH mediated DA-independent changes in the levels of transcripts of several genes in the DA-denervated striatum. Our results also implicate 5-HT as a potential player in these METH-induced alterations in gene expression because the METH injection also caused significant increases in 5-HIAA/5-HT ratios on the DA-depleted side.
authors.affiliation: Molecular Neuropsychiatry Research Branch, Intramural Research Program, National Institute on Drug Abuse/National Institutes of Health/Department of Health and Human Services, Baltimore, Maryland, United States of America. jcadet@intra.nida.nih.gov
authors.forename: Jean Lud
authors.initials: JL
authors.lastname: Cadet
authors.forename: Christie
authors.initials: C
authors.lastname: Brannock
authors.forename: Irina N
authors.initials: IN
authors.lastname: Krasnova
authors.forename: Bruce
authors.initials: B
authors.lastname: Ladenheim
authors.forename: Michael T
authors.initials: MT
authors.lastname: McCoy
authors.forename: Jenny
authors.initials: J
authors.lastname: Chou
authors.forename: Elin
authors.initials: E
authors.lastname: Lehrmann
authors.forename: William H
authors.initials: WH
authors.lastname: Wood
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Becker
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003342:Corpus Striatum / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D051766:Early Growth Response Protein 1 / Q000096:biosynthesis; D005786:Gene Expression Regulation; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D020411:Oligonucleotide Array Sequence Analysis; D016627:Oxidopamine / Q000737:chemistry / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004268:DNA-Binding Proteins; D018765:Dopamine Uptake Inhibitors; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D009419:Nerve Tissue Proteins; C091333:Nr4a3 protein, rat; D016760:Proto-Oncogene Proteins c-fos; D008694:Methamphetamine; D016627:Oxidopamine; D004298:Dopamine