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PMID: 12716423 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Molecular profiling of midbrain dopamine regions in cocaine overdose victims.

Journal of neurochemistry ·Vol. 85 ·No. 4 ·2003-05-00 ·Pages 911-24

Tang WX, Fasulo WH, Mash DC, Hemby SE

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.

MeSH Terms
Adult Cocaine/poisoning Cyclic AMP Response Element-Binding Protein/analysis Dopamine/physiology Drug Overdose Female GTP-Binding Proteins/analysis Gene Expression Profiling Humans Male Mesencephalon/chemistry,drug effects,pathology Middle Aged Oligonucleotide Array Sequence Analysis RNA Processing, Post-Transcriptional/drug effects RNA, Messenger/analysis,genetics Receptors, AMPA/genetics Receptors, Kainic Acid/genetics Receptors, N-Methyl-D-Aspartate/genetics Signal Transduction/drug effects Substantia Nigra/chemistry,drug effects,pathology Up-Regulation/drug effects Ventral Tegmental Area/chemistry,drug effects,pathology
Chemicals
Cyclic AMP Response Element-Binding Protein NR1 NMDA receptor RNA, Messenger Receptors, AMPA Receptors, Kainic Acid Receptors, N-Methyl-D-Aspartate GTP-Binding Proteins Cocaine glutamate receptor ionotropic, AMPA 2 Dopamine
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Tang Wen-Xue
Department of Pharmacology and Psychiatry/Behavioral Sciences, Yerkes National Primate Research Center, Neuroscience Division, Emory University School of Medicine, 954 Gatewood Road, Atlanta, GA 30329, USA.
Fasulo Wendy H
Mash Deborah C
Hemby Scott E
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Article Info
Journal
Journal of neurochemistry
Abbr.
J Neurochem
ISSN
0022-3042
DOI
10.1046/j.1471-4159.2003.01740.x
Published
2003-05-00
Pages
911-24
Language
English
Region
England
NLM ID
2985190R
PMCID
PMC3843357
Subset
IM
Grants
NIDA NIH HHS · F31 DA015941 · United States
NIDA NIH HHS · R01 DA013772-03 · United States
NIDA NIH HHS · DA 13772 · United States
NIDA NIH HHS · F31 DA 15941 · United States
External Links
PubMed source DOI: 10.1046/j.1471-4159.2003.01740.x PMC Full Text View journal details
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