Molecular profiling of midbrain dopamine regions in cocaine overdose victims

• Type of Material: Article
• Authors: Wen-Xue Tang, Emory University; Wendy H. Fasulo, Emory University; Deborah C. Mash, University of Miami; Scott E. Hemby, Emory University
• Language: English
• Date: 2003-05
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2003 International Society for Neurochemistry
• Final Published Version (URL): http://onlinelibrary.wiley.com/doi/10.1046/j.1471-4159.2003.01740.x/abstract
• Title of Journal or Parent Work: Journal of Neurochemistry
• ISSN: 0022-3042
• Volume: 85
• Issue: 4
• Start Page: 911
• End Page: 924
• Grant/Funding Information: This work was supported in part by grants from the National Institute on Drug Abuse (DA13772, SEH; F31 DA15941, WHF). The Emory University Health Sciences Center Microarray Facility provided the cDNA clones.
• Keywords: cocaine; substantia nigra; gene expression; glutamate; ventral tegmental area; CREB
• Research Categories: Health Sciences, Pharmacology; Psychology, Behavioral; Biology, Neuroscience

Abstract

Chronic cocaine use in humans and animal models is known to lead to pronounced alterations in neuronal function in brain regions associated with drug reinforcement. To evaluate whether the alterations in gene expression in cocaine overdose victims are associated with specific dopamine populations in the midbrain, cDNA arrays and western blotting were used to compare gene and protein expression patterns between cocaine overdose victims and age-matched controls in the ventral tegmental area (VTA) and lateral substantia nigra (l-SN). Array analysis revealed significant up-regulation of numerous transcripts in the VTA, but not in the l-SN, of cocaine overdose victims including NMDAR1, GluR2, GluR5 and KA2 receptor mRNA (p < 0.05). No significant alterations between overdose victims and controls were observed for GluR1, R3 or R4 mRNA levels. Correspondingly, western blot analysis revealed VTA-selective up-regulation of CREB (p < 0.01), NMDAR1 (p < 0.01), GluR2 (p < 0.05), GluR5 (p < 0.01) and KA2 (p < 0.05) protein levels of cocaine overdose victims. The present results indicate that selective alterations of CREB and certain ionotropic glutamate receptor (iGluR) subtypes appear to be associated with chronic cocaine use in humans in a region-specific manner. Moreover, as subunit composition determines the functional properties of iGluRs, the observed changes may indicate alterations in the excitability of dopamine transmission underlying long-term biochemical and behavioral effects of cocaine in humans.