PMID- 24183790 OWN - NLM STAT- MEDLINE DCOM- 20150219 LR - 20211021 IS - 1873-2402 (Electronic) IS - 0006-3223 (Print) IS - 0006-3223 (Linking) VI - 76 IP - 1 DP - 2014 Jul 1 TI - Methamphetamine-associated memory is regulated by a writer and an eraser of permissive histone methylation. PG - 57-65 LID - 10.1016/j.biopsych.2013.09.014 [doi] AB - BACKGROUND: Memories associated with drugs of abuse, such as methamphetamine (METH), increase relapse vulnerability to substance use disorder by triggering craving. The nucleus accumbens (NAc) is essential to these drug-associated memories, but underlying mechanisms are poorly understood. Posttranslational chromatin modifications, such as histone methylation, modulate gene transcription; thus, we investigated the role of the associated epigenetic modifiers in METH-associated memory. METHODS: Conditioned place preference was used to assess the epigenetic landscape in the NAc supporting METH-associated memory (n = 79). The impact of histone methylation (H3K4me2/3) on the formation and expression of METH-associated memory was determined by focal, intra-NAc knockdown (KD) of a writer, the methyltransferase mixed-lineage leukemia 1 (Mll1) (n = 26), and an eraser, the histone lysine (K)-specific demethylase 5C (Kdm5c) (n = 38), of H3K4me2/3. RESULTS: A survey of chromatin modifications in the NAc of animals forming a METH-associated memory revealed the global induction of several modifications associated with active transcription. This correlated with a pattern of gene activation, as revealed by microarray analysis, including upregulation of oxytocin receptor (Oxtr) and FBJ osteosarcoma oncogene (Fos), the promoters of which also had increased H3K4me3. KD of Mll1 reduced H3K4me3, Fos and Oxtr levels and disrupted METH-associated memory. KD of Kdm5c resulted in hypermethylation of H3K4 and prevented the expression of METH-associated memory. CONCLUSIONS: The development and expression of METH-associated memory are supported by regulation of H3K4me2/3 levels by MLL1 and KDM5C, respectively, in the NAc. These data indicate that permissive histone methylation, and the associated epigenetic writers and erasers, represent potential targets for the treatment of substance abuse relapse, a psychiatric condition perpetuated by unwanted associative memories. CI - (c) 2013 Society of Biological Psychiatry Published by Society of Biological Psychiatry All rights reserved. FAU - Aguilar-Valles, Argel AU - Aguilar-Valles A AD - Department of Metabolism and Aging, The Scripps Research Institute, Florida. AD - Department of Neuroscience, The Scripps Research Institute, Florida. FAU - Vaissiere, Thomas AU - Vaissiere T AD - Department of Metabolism and Aging, The Scripps Research Institute, Florida. AD - Department of Neuroscience, The Scripps Research Institute, Florida. FAU - Griggs, Erica M AU - Griggs EM AD - Department of Metabolism and Aging, The Scripps Research Institute, Florida. AD - Department of Neuroscience, The Scripps Research Institute, Florida. FAU - Mikaelsson, Mikael A AU - Mikaelsson MA AD - Department of Metabolism and Aging, The Scripps Research Institute, Florida. AD - Department of Neuroscience, The Scripps Research Institute, Florida. FAU - Takacs, Irma F AU - Takacs IF AD - Department of Metabolism and Aging, The Scripps Research Institute, Florida. AD - Department of Neuroscience, The Scripps Research Institute, Florida. FAU - Young, Erica J AU - Young EJ AD - Department of Metabolism and Aging, The Scripps Research Institute, Florida. AD - Department of Neuroscience, The Scripps Research Institute, Florida. FAU - Rumbaugh, Gavin AU - Rumbaugh G AD - Department of Neuroscience, The Scripps Research Institute, Florida. FAU - Miller, Courtney A AU - Miller CA AD - Department of Metabolism and Aging, The Scripps Research Institute, Florida. AD - Department of Neuroscience, The Scripps Research Institute, Florida. LA - eng GR - R00 DA024761/DA/NIDA NIH HHS/United States GR - DA033499/DA/NIDA NIH HHS/United States GR - DA034116/DA/NIDA NIH HHS/United States GR - K99 DA024761/DA/NIDA NIH HHS/United States GR - R03 DA033499/DA/NIDA NIH HHS/United States GR - R01 MH096847/MH/NIMH NIH HHS/United States GR - R01 DA034116/DA/NIDA NIH HHS/United States GR - DA024761/DA/NIDA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20131031 PL - United States TA - Biol Psychiatry JT - Biological psychiatry JID - 0213264 RN - 0 (Chromatin) RN - 0 (Histones) RN - 149025-06-9 (Myeloid-Lymphoid Leukemia Protein) RN - 44RAL3456C (Methamphetamine) RN - EC 1.14.11.- (Histone Demethylases) RN - EC 1.14.11.- (Kdm5c protein, mouse) RN - EC 1.5.- (Oxidoreductases, N-Demethylating) RN - EC 2.1.1.43 (Histone-Lysine N-Methyltransferase) RN - EC 2.1.1.43 (Kmt2a protein, mouse) SB - IM MH - Animals MH - Chromatin/metabolism MH - Conditioning, Classical/drug effects/physiology MH - Epigenesis, Genetic/*drug effects/physiology MH - Gene Knockdown Techniques MH - Histone Demethylases MH - Histone-Lysine N-Methyltransferase/genetics/physiology MH - Histones/*drug effects/*metabolism MH - Male MH - Memory/*drug effects/physiology MH - Methamphetamine/*pharmacology MH - Methylation/drug effects MH - Mice MH - Myeloid-Lymphoid Leukemia Protein/genetics/physiology MH - Nucleus Accumbens/drug effects/metabolism MH - Oxidoreductases, N-Demethylating/genetics/physiology MH - Transcriptional Activation/drug effects/physiology PMC - PMC4024089 MID - NIHMS528001 OTO - NOTNLM OT - Demethylase OT - KDM5C OT - MLL OT - epigenetics OT - methyltransferase OT - nucleus accumbens EDAT- 2013/11/05 06:00 MHDA- 2015/02/20 06:00 PMCR- 2015/07/01 CRDT- 2013/11/05 06:00 PHST- 2013/06/25 00:00 [received] PHST- 2013/08/29 00:00 [revised] PHST- 2013/09/18 00:00 [accepted] PHST- 2013/11/05 06:00 [entrez] PHST- 2013/11/05 06:00 [pubmed] PHST- 2015/02/20 06:00 [medline] PHST- 2015/07/01 00:00 [pmc-release] AID - S0006-3223(13)00855-X [pii] AID - 10.1016/j.biopsych.2013.09.014 [doi] PST - ppublish SO - Biol Psychiatry. 2014 Jul 1;76(1):57-65. doi: 10.1016/j.biopsych.2013.09.014. Epub 2013 Oct 31.