Epigenetic basis of opiate suppression of Bdnf gene expression in the ventral tegmental area

Brain-derived neurotrophic factor (BDNF) plays a crucial role in modulating neural and behavioral plasticity to drugs of abuse. Here, we demonstrate a persistent down-regulation of exon-specific Bdnf expression in the ventral tegmental area (VTA) in response to chronic opiate exposure, which is mediated by specific epigenetic modifications at the corresponding Bdnf gene promoters. Exposure to chronic morphine increases stalling of RNA polymerase II at these Bdnf promoters in VTA and alters permissive and repressive histone modifications and occupancy of their regulatory proteins at the specific promoters. Furthermore, we show that morphine suppresses binding of phospho-CREB (cAMP response element binding protein) to Bdnf promoters in VTA, which results from enrichment of trimethylated H3K27 at the promoters, and that decreased NURR1 (nuclear receptor related-1) expression also contributes to Bdnf repression and associated behavioral plasticity to morphine. These studies reveal novel epigenetic mechanisms of morphine-induced molecular and behavioral neuroadaptations.