Transcriptional and epigenetic mechanisms of drug addiction

Drug addiction can be viewed as a stable form of drug-induced neural plasticity, whereby long-lasting changes in gene expression mediate some of the stable behavioral abnormalities that define an addicted state. Our laboratory has focused on two main transcriptional pathways in addiction. Chronic exposure to cocaine or opiates causes the prolonged activation of the transcription factor CREB within the brain’s reward circuits and several other brain regions, and this adaptation mediates aspects of drug tolerance and dependence. In contrast, induction of another transcription factor, DeltaFosB, in brain reward regions by virtually all drugs of abuse exerts the opposite effect and contributes to sensitized responses to drug exposure. 

Studies are underway to explore the detailed molecular mechanisms by which CREB and DeltaFosB regulate target genes and thereby contribute to the complex state of addiction. One way to approach such molecular mechanisms of drug action in vivo is through the study of chromatin remodeling, that is, changes in the acetylation or methylation of histones that bind to certain drug-regulated gene promoters, or changes in methylation of the promoters themselves, as revealed by chromatin immunoprecipitation (ChIP). We are utilizing ChIP to examine chromatin changes at specific candidate genes for CREB and DeltaFosB, as well as genome-wide measures to gain a more global view of target genes for these transcription factors. Prominent among these targets are those that regulate synaptic function and plasticity as well as the morphology of drug-regulated neurons. We have also demonstrated drug regulation of some of the enzymes that catalyze chromatin modifications, which indicates that chromatin remodeling mechanisms are themselves important targets of drug action. 

These findings establish chromatin remodeling as an important regulatory mechanism underlying drug-induced neural and behavioral plasticity, and provide fundamentally new insight into how CREB and DeltaFosB, and several other drug-regulated transcription factors, contribute to addiction by regulating the expression of specific target genes in the brain’s reward circuitry. These advances can now be mined to develop improved diagnostic tests and treatments for addictive disorders.