Opioid gene expression changes and post-translational histone modifications at promoter regions in the rat nucleus accumbens after acute and repeated 3,4-methylenedioxy-methamphetamine (MDMA) exposure

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• 作者：Francesca Felicia Caputi ; Martina Palmisano ; Lucia Carboni ; Sanzio Candeletti¹ ; Patrizia Romualdi ; ¹ ; ^{patrizia.romualdi@unibo.it}
• 关键词：5HT ; serotonin ; BSA ; bovine serum albumin ; ChIP ; chromatin immunoprecipitation ; CPP ; conditioned place preference ; CREB ; cyclic-AMP response-element-binding protein ; DA ; dopamine ; DDCt ; delta&ndash ; delta threshold cycle ; DYN ; dynorphin ; GAPDH ; glyceraldehyde-3-phosphate dehydrogenase ; H ; histone ; K ; lysine ; KOP ; κ-opioid receptor ; MDMA ; 3 ; 4-methylenedioxy-methamphetamine ; N/OFQ ; nociceptin/orphaninFQ ; NOP ; nociceptin receptor ; PBS ; phosphate-buffered saline ; PIC ; protease inhibitor cocktail ; pDY
• 刊名：Pharmacological Research
• 出版年：2016
• 出版时间：December 2016
• 年：2016
• 卷：114
• 期：Complete
• 页码：209-218
• 全文大小：1955 K
• 卷排序：114

文摘

The recreational drug of abuse 3,4-methylenedioxymethamphetamine (MDMA) has been shown to produce neurotoxic damage and long-lasting changes in several brain areas. In addition to the involvement of serotoninergic and dopaminergic systems, little information exists about the contribution of nociceptin/orphaninFQ (N/OFQ)-NOP and dynorphin (DYN)-KOP systems in neuronal adaptations evoked by MDMA. Here we investigated the behavioral and molecular effects induced by acute (8 mg/kg) or repeated (8 mg/kg twice daily for seven days) MDMA exposure.MDMA exposure affected body weight gain and induced hyperlocomotion; this latter effect progressively decreased after repeated administration. Gene expression analysis indicated a down-regulation of the N/OFQ system and an up-regulation of the DYN system in the nucleus accumbens (NAc), highlighting an opposite systems regulation in response to MDMA exposure.Since histone modifications have been strongly associated to the addiction-related maladaptive changes, we examined two permissive (acH3K9 and me3H3K4) and two repressive transcription marks (me3H3K27 and me2H3K9) at the pertinent opioid gene promoter regions. Chromatin immunoprecipitation assays revealed that acute MDMA increased me3H3K4 at the pN/OFQ, pDYN and NOP promoters. Following acute and repeated treatment a significant decrease of acH3K9 at the pN/OFQ promoter was observed, which correlated with gene expression results. Acute treatment caused an acH3K9 increase and a me2H3K9 decrease at the pDYN promoter which matched its mRNA up-regulation.Our data indicate that the activation of the DYNergic stress system together with the inactivation of the N/OFQergic anti-stress system contribute to the neuroadaptive actions of MDMA and offer novel epigenetic information associated with MDMA abuse.