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.