Investigating the Potential Influence of Cause of Death and Cocaine Levels on the Differential Expression of Genes Associated with Cocaine Abuse
Investigating the Potential Influence of Cause of Death and Cocaine Levels on the Differential Expression of Genes Associated with Cocaine Abuse
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DOI：
10.1371/journal.pone.0117580
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发表时间：
2015-02-06
期刊：
影响因子：
3.7
通讯作者：
Schmidt, Carl J.
中科院分区：
文献类型：
--
作者：
Bannon, Michael J.;Savonen, Candace L.;Schmidt, Carl J.
通过对潜在的分子病理生理学的更完整的理解，可能会促进治疗复杂脑疾病（如药物成瘾）的新治疗策略的开发。虽然死后人脑的研究在这方面代表了一个独特的资源，它可以是具有挑战性的解开慢性病理过程与围死期事件的相对贡献所观察到的基因表达的变化。为了开始解开这个问题，我们通过定量PCR分析了许多先前与可卡因滥用相关的候选基因的中脑表达。从慢性可卡因滥用者（和匹配的对照受试者）死于枪伤的数据进行了比较，与直接归因于可卡因滥用的死亡受试者的先前研究。研究的大多数基因（即，酪氨酸羟化酶、多巴胺转运蛋白、叉头框A2、组蛋白变体H3家族3 B、核因子κ B抑制剂α、生长停滞和DNA损伤诱导β）在慢性可卡因滥用者中被发现差异表达，而与死亡的直接原因或可卡因的死前水平无关，这表明这些可能代表慢性药物滥用引起的核心病理生理学变化。另一方面，趋化因子C-C基序配体2和jun原癌基因表达在可卡因滥用受试者死于枪伤中不受影响，与之前报道的可卡因相关死亡中的差异表达相反。死亡原因和其他因素对这些基因的可卡因反应性的可能影响进行了讨论。
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.