Molecular profiling of midbrain dopamine regions in cocaine overdose victims.
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.
Tang
Wen-Xue
WX
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
WH
Mash
Deborah C
DC
Hemby
Scott E
SE
D000328:Adult; D003042:Cocaine / Q000506:poisoning*; D017362:Cyclic AMP Response Element-Binding Protein / Q000032:analysis; D004298:Dopamine / Q000502:physiology; D062787:Drug Overdose; D005260:Female; D019204:GTP-Binding Proteins / Q000032:analysis; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008636:Mesencephalon / Q000737:chemistry* / Q000187:drug effects* / Q000473:pathology; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D018091:Receptors, AMPA / Q000235:genetics; D018092:Kainic Acid Receptors / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013378:Substantia Nigra / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects; D017557:Ventral Tegmental Area / Q000737:chemistry / Q000187:drug effects / Q000473:pathology
D003042:Cocaine; D017362:Cyclic AMP Response Element-Binding Protein; D004298:Dopamine; D019204:GTP-Binding Proteins; D012333:RNA, Messenger; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; C409466:NR1 NMDA receptor; C104722:glutamate receptor ionotropic, AMPA 2