title: Cocaine-induced chromatin remodeling increases brain-derived neurotrophic factor transcription in the rat medial prefrontal cortex, which alters the reinforcing efficacy of cocaine.
abstract: Cocaine self-administration alters patterns of gene expression in the brain that may underlie cocaine-induced neuronal plasticity. In the present study, male Sprague Dawley rats were allowed to self-administer cocaine (0.25 mg/infusion) 2 h/d for 14 d, followed by 7 d of forced abstinence. Compared with yoked saline control rats, cocaine self-administration resulted in increased brain-derived neurotrophic factor (BDNF) protein levels in the rat medial prefrontal cortex (mPFC). To examine the functional relevance of this finding, cocaine self-administration maintained under a progressive ratio schedule of reinforcement was assessed after short hairpin RNA-induced suppression of BDNF expression in the mPFC. Decreased BDNF expression in the mPFC increased the cocaine self-administration breakpoint. Next, the effect of cocaine self-administration on specific BDNF exons was assessed; results revealed selectively increased BDNF exon IV-containing transcripts in the mPFC. Moreover, there were significant cocaine-induced increases in acetylated histone H3 (AcH3) and phospho-cAMP response element binding protein (pCREB) association with BDNF promoter IV. In contrast, there was decreased methyl-CpG-binding protein 2 (MeCP2) association with BDNF promoter IV in the mPFC of rats that previously self-administered cocaine. Together, these results indicate that cocaine-induced increases in BDNF promoter IV transcript in the mPFC are driven by increased binding of AcH3 and pCREB as well as decreased MeCP2 binding at this BDNF promoter. Collectively, these results indicate that cocaine self-administration remodels chromatin in the mPFC, resulting in increased expression of BDNF, which appears to represent a compensatory neuroadaptation that reduces the reinforcing efficacy of cocaine.
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02129-4404, USA. gsadrivakili@partners.org
authors.forename: Ghazaleh
authors.initials: G
authors.lastname: Sadri-Vakili
authors.forename: Vidhya
authors.initials: V
authors.lastname: Kumaresan
authors.forename: Heath D
authors.initials: HD
authors.lastname: Schmidt
authors.forename: Katie R
authors.initials: KR
authors.lastname: Famous
authors.forename: Prianka
authors.initials: P
authors.lastname: Chawla
authors.forename: Fair M
authors.initials: FM
authors.lastname: Vassoler
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Overland
authors.forename: Eva
authors.initials: E
authors.lastname: Xia
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Bass
authors.forename: Ernest F
authors.initials: EF
authors.lastname: Terwilliger
authors.forename: R Christopher
authors.initials: RC
authors.lastname: Pierce
authors.forename: Jang-Ho J
authors.initials: JH
authors.lastname: Cha
mesh_terms: D000818:Animals; D016739:Behavior, Addictive / Q000378:metabolism / Q000523:psychology; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis* / Q000235:genetics*; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects* / Q000502:physiology*; D003042:Cocaine / Q000008:administration & dosage* / Q000494:pharmacology; D019970:Cocaine-Related Disorders / Q000378:metabolism / Q000523:psychology; D008297:Male; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012054:Reinforcement, Psychology; D012646:Self Administration; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D003042:Cocaine
references.citation: Pharmacol Rev. 2002 Mar;54(1):1-42
references.pmid: 11870259
references.citation: Eur J Neurosci. 2002 Jun;15(12):2016-26
references.pmid: 12099907
references.citation: Mol Psychiatry. 1996 Jul;1(3):190-9
references.pmid: 9118343
references.citation: J Neurosci. 2002 May 1;22(9):3663-72
references.pmid: 11978842
references.citation: Neuropsychopharmacology. 2003 Aug;28(8):1485-90
references.pmid: 12784114
references.citation: Neuroscience. 2001;108(3):371-80
references.pmid: 11738252
references.citation: Science. 2003 Oct 31;302(5646):885-9
references.pmid: 14593183
references.citation: Psychol Rev. 1974 Mar;81(2):119-45
references.pmid: 4817611
references.citation: J Neurosci. 1994 Mar;14(3 Pt 1):1262-70
references.pmid: 8074747
references.citation: Trends Neurosci. 2005 Aug;28(8):436-45
references.pmid: 15982754
references.citation: J Neurosci. 2005 Dec 7;25(49):11444-54
references.pmid: 16339038
references.citation: Nat Neurosci. 2005 Nov;8(11):1440-1
references.pmid: 16251984
references.citation: Nat Neurosci. 2005 Nov;8(11):1437-9
references.pmid: 16251983
references.citation: J Neurosci. 2009 Mar 25;29(12):3715-9
references.pmid: 19321768
references.citation: J Neurosci. 2008 Jan 30;28(5):1118-30
references.pmid: 18234890
references.citation: J Virol. 1998 Mar;72(3):2224-32
references.pmid: 9499080
references.citation: Am J Psychiatry. 2005 Aug;162(8):1473-82
references.pmid: 16055768
references.citation: Eur J Neurosci. 2007 Nov;26(10):2756-63
references.pmid: 18001273
references.citation: J Neurosci. 2006 Sep 20;26(38):9656-65
references.pmid: 16988036
references.citation: J Neurosci. 2008 Sep 17;28(38):9342-8
references.pmid: 18799668
references.citation: Mol Ther. 2006 Jan;13(1):67-76
references.pmid: 16260185
references.citation: Eur J Neurosci. 1996 Aug;8(8):1696-706
references.pmid: 8921260
references.citation: Neuroreport. 2005 Feb 8;16(2):175-8
references.pmid: 15671872
references.citation: Addict Biol. 2005 Mar;10(1):101-18
references.pmid: 15849024
references.citation: Brain Res. 2010 Feb 16;1314:183-93
references.pmid: 19732758
references.citation: Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11024-31
references.pmid: 11572963
references.citation: J Pharmacol Exp Ther. 2003 Nov;307(2):450-9
references.pmid: 12966149
references.citation: Nat Neurosci. 2007 Aug;10(8):1029-37
references.pmid: 17618281
references.citation: Brain Res. 1997 Feb 21;749(1):120-6
references.pmid: 9070635
references.citation: Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11854-9
references.pmid: 12192090
references.citation: Nat Rev Neurosci. 2004 Jun;5(6):483-94
references.pmid: 15152198
references.citation: Proc Natl Acad Sci U S A. 2005 Dec 27;102(52):19186-91
references.pmid: 16380431
references.citation: Neuron. 2005 Oct 20;48(2):303-14
references.pmid: 16242410
references.citation: J Neurosci. 2004 Feb 18;24(7):1604-11
references.pmid: 14973246
references.citation: Neurosci Biobehav Rev. 2006;30(2):215-38
references.pmid: 16099045
references.citation: Hum Mol Genet. 2007 Jun 1;16(11):1293-306
references.pmid: 17409194
references.citation: J Neurosci. 1999 May 15;19(10):4110-22
references.pmid: 10234039
references.citation: J Neurosci Methods. 1980 Dec;3(2):129-49
references.pmid: 6110810
references.citation: Nat Neurosci. 2005 Nov;8(11):1445-9
references.pmid: 16251986
references.citation: Mol Pharmacol. 2006 Aug;70(2):487-92
references.pmid: 16670375
references.citation: Science. 2003 Oct 31;302(5646):890-3
references.pmid: 14593184
references.citation: Hum Gene Ther. 1999 Apr 10;10(6):1031-9
references.pmid: 10223736
references.citation: J Neurosci Res. 2007 Feb 15;85(3):525-35
references.pmid: 17149751
references.citation: Methods Mol Biol. 2004;277:261-76
references.pmid: 15201461
references.citation: J Neurosci. 1999 Oct 1;19(19):8685-95
references.pmid: 10493769
references.citation: Neurobiol Dis. 2006 May;22(2):233-41
references.pmid: 16442295
references.citation: Brain Res. 2006 Jan 5;1067(1):1-12
references.pmid: 16376315
references.citation: Eur J Neurosci. 2007 Aug;26(3):757-66
references.pmid: 17651427
references.citation: J Neurochem. 2003 May;85(4):911-24
references.pmid: 12716423
references.citation: Neuron. 2007 Nov 8;56(3):517-29
references.pmid: 17988634
references.citation: J Neurosci Methods. 1996 May;66(1):1-11
references.pmid: 8794935
references.citation: Brain Res Mol Brain Res. 1994 Feb;21(3-4):206-18
references.pmid: 8170345
references.citation: Neuropharmacology. 2004;47 Suppl 1:24-32
references.pmid: 15464123
references.citation: J Neurosci. 2003 Feb 1;23(3):742-7
references.pmid: 12574402
references.citation: J Psychopharmacol. 1999 Dec;13(4):337-45
references.pmid: 10667609
references.citation: Neuropsychopharmacology. 2008 Jul;33(8):1807-17
references.pmid: 17851536
references.citation: J Neurochem. 2002 Sep;82(6):1453-64
references.pmid: 12354293
references.citation: Biol Psychiatry. 2007 Jul 1;62(1):55-64
references.pmid: 16945350
references.citation: Neuron. 1993 Mar;10(3):475-89
references.pmid: 8461137