Investigating the potential influence of cause of death and cocaine levels on the differential expression of genes associated with cocaine abuse.

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.

A molecular profile of cocaine abuse includes the differential expression of genes that regulate transcription, chromatin, and dopamine cell phenotype.

Chronic drug abuse, craving, and relapse are thought to be linked to long-lasting changes in neural gene expression arising through transcriptional and chromatin-related mechanisms. The key contributions of midbrain dopamine (DA)-synthesizing neurons throughout the addiction process provide a compelling rationale for determining the drug-induced molecular changes that occur in these cells. Yet our understanding of these processes remains rudimentary.

Increased heat shock protein 70 gene expression in the brains of cocaine-related fatalities may be reflective of postdrug survival and intervention rather than excited delirium.

Cocaine-related fatalities can pose forensic challenges, particularly when accompanied by excited delirium (ED) syndrome and interventions by law enforcement and medical personnel. A recent report concluded that elevated heat shock protein 70 (HSP70) expression in autopsy brain samples constitutes a reliable forensic biomarker for the identification of ED as a cause of death. The present study quantified the abundance of both HSPA1A and HSPA1B gene (HSP70-encoding) transcripts in midbrain specimens from a series of cocaine-related fatalities and matched drug-free control subjects.

The Transcription Factor NURR1 Exerts Concentration-Dependent Effects on Target Genes Mediating Distinct Biological Processes.

The transcription factor NURR1 plays a pivotal role in the development and maintenance of neurotransmitter phenotype in midbrain dopamine neurons. Conversely, decreased NURR1 expression is associated with a number of dopamine-related CNS disorders, including Parkinson's disease and drug addiction. In order to better understand the nature of NURR1-responsive genes and their potential roles in dopamine neuron differentiation and survival, we used a human neural cellular background (SK-N-AS cells) in which to generate a number of stable clonal lines with graded NURR1 gene expression that approximated that seen in DA cell-rich human substantia nigra.