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

Abstract

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.

Update of neurotrophic factors in neurobiology of addiction and future directions

“…Furthermore, morphine seems to suppress the binding of phospho-CREB (cAMP response element-binding protein) and NURR1 (nuclear receptor related-1) to Bdnf promoters in the VTA, resulting in decreased expression of BDNF. In line with this, overexpression of NURR1 in the VTA was shown to decrease morphine-induced place preference, whereas a local knockout of Bdnf could abolish this effect (Koo et al, 2015). …”

“…Quantitative chromatin immunoprecipitation with antibodies recognizing differentially phosphorylated forms of RNA polymerase II together with a comprehensive analysis of epigenetic regulation of Bdnf gene suggested that exposure to chronic morphine can increase the stalling of RNA polymerase II at Bdnf promoters in the rat VTA (Koo et al, 2015). Furthermore, morphine seems to suppress the binding of phospho-CREB (cAMP response element-binding protein) and NURR1 (nuclear receptor related-1) to Bdnf promoters in the VTA, resulting in decreased expression of BDNF.…”

Brain-Derived Neurotrophic Factor in the Mesolimbic Reward Circuitry Mediates Nociception in Chronic Neuropathic Pain

“…However, less information is available at the supraspinal level, especially in the mesolimbic reward circuitry. As previously mentioned, BDNF signaling within the mesolimbic reward system has been implicated in several neuropsychological disorders (15, 25, 28, 31–33, 55, 58). Here, we found that 1) CCI-induced BDNF protein expression and release in the NAc depended on VTA DA neuron activity; 2) the inhibition of VTA DA neuron firing reversed the established thermal hyperalgesia in CCI mice, which was restored by microinjecting exogenous BDNF into the NAc; 3) the blockade of BDNF signaling in the NAc and inhibition of synthesis in the VTA produced analgesia effects, which were reversed by injecting BDNF directly into the NAc; and 4) selective knockdown of BDNF expression in NAc-projecting VTA neurons reversed CCI-induced thermal hyperalgesia.…”

Blocking microglial pannexin-1 channels alleviates morphine withdrawal in rodents

“…This form of neuronal hyperexcitability is a cardinal feature of withdrawal 14,22 , and we demonstrate here that this central tenet of withdrawal occurs directly in the spinal cord of morphine-treated animals. Because opiate withdrawal engages both spinal and supraspinal mechanisms, including the periaqueductal gray 14 , locus coeruleus 23 , ventral tegmental area [24][25][26] and nucleus accumbens 27 , descending inputs from these supraspinal regions may influence spinal facilitation in the intact system. However, our isolated spinal cord preparation suggests that intrinsic spinal mechanisms are sufficient for synaptic facilitation during withdrawal, and as further evidence for a spinal locus of opiate action, we show that spinal manipulations targeting Panx1 channels or ATP levels effectively block or recapitulate the behavioral and cellular corollaries of withdrawal.…”