Identification of differentially regulated transcripts in mouse striatum following methamphetamine treatment – an oligonucleotide microarray approach

Abstract

Methamphetamine is an addictive drug of abuse that can produce neurotoxic effects in dopamine nerve endings of the striatum. The purpose of this study was to identify new genes that may play a role in the highly complex cascade of events associated with methamphetamine intoxication. Using Affymetrix oligonucleotide arrays, 12 488 genes were simultaneously interrogated and there were 152 whose expression levels were changed following methamphetamine treatment. The genes are grouped into broad functional categories with inflammatory/immune response elements, receptor/signal transduction components and ion channel/transport proteins among the most populated. Many genes within these categories can be linked to ion regulation and apoptosis, both of which have been implicated in methamphetamine toxicity, and numerous factors associated with microglial activation emerged with significant changes in expression. For example, brain-derived neurotrophic factor (BDNF) 2, chemokine (C-C) receptor 6 (CCr6) and numerous chemokine transcripts were increased or decreased in expression more than 2.8-fold. These results point to activated microglia as a potential source of the reactive oxygen/nitrogen species and cytokines that have been previously associated with methamphetamine toxicity and other neurotoxic conditions.

Cyclooxygenase-2 Is an Obligatory Factor in Methamphetamine-Induced Neurotoxicity

“…COX-2 expression continued to increase up to 48 h after treatment, reaching a peak of 390% of control at 24 h. The levels of COX-1 protein were not changed by METH over the same time course. These results are in good agreement with our previous finding that COX-2 gene expression is increased by METH, whereas COX-1 gene expression remains unchanged (Thomas et al, 2004a). Using the time point of peak expression (24 h), we examined COX-2 protein levels in the wildtype littermates of COX-1 and COX-2 knockout mice (Fig.…”

“…This situation is somewhat surprising in view of the larger role of the prostanoids in mediating other forms of neuronal injury, inflammation, and degeneration (Hurley et al, 2002). A comprehensive analysis of gene expression changes provoked by a neurotoxic regimen of METH substantiated these earlier findings by showing a drug-induced increase in expression of the genes for COX-2 and C/EBP (Thomas et al, 2004a). These initial gene expression results are extended presently by the demonstration that METH intoxication induces the expression of COX-2 protein.…”

“…Clues for a new mediator of METH neurotoxicity emerged from a recent microarray analysis of drug-induced changes in gene expression. We found that a neurotoxic regimen of METH increased expression of the genes for transcription factor CCAAT/enhancer-binding protein (C/EBP) and COX-2 (Thomas et al, 2004a). The COX enzymes are the obligatory step in prostaglandin biosynthesis and exist in two major isoforms: COX-1 is constitutively expressed, whereas COX-2 expression is inducible (Smith et al, 2000).…”

Direct Evidence of Astrocytic Modulation in the Development of Rewarding Effects Induced by Drugs of Abuse

“…They are expressed at constitutively low levels in microglia, and induced by inflammatory mediators (Mennicken et al, 1999;Färber and Kettenmann, 2005). Moreover, microglial cells are known to response to drugs of abuse, such as MRP and METH (Guilarte et al, 2003;Thomas et al, 2004;Khurdayan et al, 2004). In the present study, treatment with METH caused a morphological change in purified microglia, whereas MRP had no such effect.…”

Effects of Methamphetamine Dependence and HIV Infection on Cerebral Morphology

“…In addition to these animal studies of sprouting in the striatum, several studies have demonstrated pronounced effects on microglial activation in methamphetamineexposed rodents (31,32), both in the striatum and, specifically, in the somatosensory cortex; these studies have suggested a role for microglial activation in methamphetamine neurotoxicity. Microglial activation has also been linked to astrocytosis (33), and both astrocytosis and depletion of glutamate-staining neurons have been observed in the somatosensory cortex of methamphetamine-exposed animals (34).…”