Epigenetic Regulation in Substance Use Disorders

Substance use disorder is a chronic condition of compulsive drug seeking and use that is mediated by stable changes in central reward pathways. Repeated use of abused drugs causes persistent alterations in gene expression responsible for the long-term behavioral and structural changes. Recently, it has been suggested that epigenetic mechanisms are responsible in part for these drug-induced changes in gene expression. One of the alluring aspects of epigenetic regulation of gene expression is that epigenetic mechanisms may provide transient and potentially stable conditions that in turn may ultimately participate in the molecular mechanisms required for neuronal changes subserving long-lasting changes in behavior. This review describes epigenetic mechanisms of gene regulation and then discusses the emerging role of epigenetics in drug-induced plasticity and behavior. Understanding these mechanisms that establish and maintain drug-dependent plasticity changes may lead to deeper understanding of substance use disorders as well as novel approaches to treatment.     

Chromatin regulation in drug addiction and depression

Alterations in gene expression are implicated in the pathogenesis of several neuropsychiatrie disorders, including drug addiction and depression, increasing evidence indicates that changes in gene expression in neurons, in the context of animal models of addiction and depression, are mediated in part by epigenetic mechanisms that alter chromatin structure on specific gene promoters. This review discusses recent findings from behavioral, molecular, and bioinformatic approaches that are being used to understand the complex epigenetic regulation of gene expression in brain by drugs of abuse and by stress. These advances promise to open up new avenues for improved treatments of these disorders.     

Identification of two novel diurnal genes by screening of a rat brain cDNA library.

While the hypothalamus is fundamental for sleep and circadian regulation, the molecular mechanism involved are poorly understood. We have used a differential gene expression technique to identify hypothalamic genes which have altered expression in rat sleep periods. Complex cDNA probes from rat hypothalami removed at Zeitgeber times 4 and 15 were hybridised to rat brain cDNA library girds. From 30 differentially expressed clones, six were further analysed and two were confirmed to exhibit increased expression at Zeitgeber time 4. A Northern blot hybridization of brain, heart, kidney, lung, testis and skin mRNA showed that both clones were brain specific. Therefore, we have identified two novel brain specific diurnally expressed hypothalamic genes. Both genes may have roles in sleep or circadian regulation.     

Epigenetic regulation of the BDNF gene: implications for psychiatric disorders

Abnormal brain-derived neurotrophic factor (BDNF) signaling seems to have a central role in the course and development of various neurological and psychiatric disorders. In addition, positive effects of psychotropic drugs are known to activate BDNF-mediated signaling. Although the BDNF gene has been associated with several diseases, molecular mechanisms other than functional genetic variations can impact on the regulation of BDNF gene expression and lead to disturbed BDNF signaling and associated pathology. Thus, epigenetic modifications, representing key mechanisms by which environmental factors induce enduring changes in gene expression, are suspected to participate in the onset of various psychiatric disorders. More specifically, various environmental factors, particularly when occurring during development, have been claimed to produce long-lasting epigenetic changes at the BDNF gene, thereby affecting availability and function of the BDNF protein. Such stabile imprints on the BDNF gene might explain, at least in part, the delayed efficacy of treatments as well as the high degree of relapses observed in psychiatric disorders. Moreover, BDNF gene has a complex structure displaying differential exon regulation and usage, suggesting a subcellular- and brain region-specific distribution. As such, developing drugs that modify epigenetic regulation at specific BDNF exons represents a promising strategy for the treatment of psychiatric disorders. Here, we present an overview of the current literature on epigenetic modifications at the BDNF locus in psychiatric disorders and related animal models.