title: Investigating the potential influence of cause of death and cocaine levels on the differential expression of genes associated with cocaine abuse.
abstract: The development of new therapeutic strategies for the treatment of complex brain disorders such as drug addiction is likely to be advanced by a more complete understanding of the underlying molecular pathophysiology. Although the study of postmortem human brain represents a unique resource in this regard, it can be challenging to disentangle the relative contribution of chronic pathological processes versus perimortem events to the observed changes in gene expression. To begin to unravel this issue, we analyzed by quantitative PCR the midbrain expression of numerous candidate genes previously associated with cocaine abuse. Data obtained from chronic cocaine abusers (and matched control subjects) dying of gunshot wounds were compared with a prior study of subjects with deaths directly attributable to cocaine abuse. Most of the genes studied (i.e., tyrosine hydroxylase, dopamine transporter, forkhead box A2, histone variant H3 family 3B, nuclear factor kappa B inhibitor alpha, growth arrest and DNA damage-inducible beta) were found to be differentially expressed in chronic cocaine abusers irrespective of immediate cause of death or perimortem levels of cocaine, suggesting that these may represent core pathophysiological changes arising with chronic drug abuse. On the other hand, chemokine C-C motif ligand 2 and jun proto-oncogene expression were unaffected in cocaine-abusing subjects dying of gunshot wounds, in contrast to the differential expression previously reported in cocaine-related fatalities. The possible influence of cause of death and other factors on the cocaine-responsiveness of these genes is discussed.
authors: Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan, United States of America.
authors: Michael J
authors: MJ
authors: Bannon
authors: Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan, United States of America.
authors: Candace L
authors: CL
authors: Savonen
authors: Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan, United States of America.
authors: Zachary J
authors: ZJ
authors: Hartley
authors: Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan, United States of America.
authors: Magen M
authors: MM
authors: Johnson
authors: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors: Carl J
authors: CJ
authors: Schmidt
mesh_terms: D000328:Adult; D000943:Antigens, Differentiation / Q000235:genetics; D001344:Autopsy; D002423:Cause of Death; D003042:Cocaine / Q000506:poisoning*; D019970:Cocaine-Related Disorders / Q000209:etiology / Q000235:genetics* / Q000401:mortality; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics; D018765:Dopamine Uptake Inhibitors / Q000506:poisoning; D059290:Dopaminergic Neurons / Q000378:metabolism; D020869:Gene Expression Profiling; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics; D008297:Male; D008636:Mesencephalon / Q000187:drug effects* / Q000378:metabolism; D008875:Middle Aged; D000072000:NF-KappaB Inhibitor alpha; D000090063:Proto-Oncogene Mas; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics; D014948:Wounds, Gunshot; D055815:Young Adult; D000097642:GADD45 Proteins
chemical_list: D000943:Antigens, Differentiation; D003042:Cocaine; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D051542:Hepatocyte Nuclear Factor 3-beta; D020672:I-kappa B Proteins; D000072000:NF-KappaB Inhibitor alpha; D000090063:Proto-Oncogene Mas; D014446:Tyrosine 3-Monooxygenase; C496502:FOXA2 protein, human; C086470:GADD45B protein, human; D000097642:GADD45 Proteins; C000715470:MAS1 protein, human; C000606204:NFKBIA protein, human