RESUMEN
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.
Asunto(s)
Trastornos Relacionados con Cocaína/genética , Cocaína/envenenamiento , Perfilación de la Expresión Génica , Mesencéfalo/efectos de los fármacos , Adulto , Antígenos de Diferenciación/genética , Autopsia , Causas de Muerte , Trastornos Relacionados con Cocaína/etiología , Trastornos Relacionados con Cocaína/mortalidad , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Inhibidores de Captación de Dopamina/envenenamiento , Neuronas Dopaminérgicas/metabolismo , Factor Nuclear 3-beta del Hepatocito/genética , Humanos , Proteínas I-kappa B/genética , Masculino , Mesencéfalo/metabolismo , Persona de Mediana Edad , Inhibidor NF-kappaB alfa , Proto-Oncogenes Mas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tirosina 3-Monooxigenasa/genética , Heridas por Arma de Fuego , Adulto JovenRESUMEN
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. The postmortem human brain constitutes a unique resource that can be exploited to gain insights into the pathophysiology of complex disorders such as drug addiction. In this study, we analyzed the profiles of midbrain gene expression in chronic cocaine abusers and well-matched drug-free control subjects using microarray and quantitative PCR. A small number of genes exhibited robust differential expression; many of these are involved in the regulation of transcription, chromatin, or DA cell phenotype. Transcript abundances for approximately half of these differentially expressed genes were diagnostic for assigning subjects to the cocaine-abusing vs control cohort. Identification of a molecular signature associated with pathophysiological changes occurring in cocaine abusers' midbrains should contribute to the development of biomarkers and novel therapeutic targets for drug addiction.