Drug addiction is marked by a conditioned physiological response and intense craving when abusers encounter stimuli associated with the drug's rewarding effects. Memory of these drug-paired cues is highly resistant to extinction and is a major contributor to relapse. Understanding on a molecular and cellular level how these factors promote relapse, despite negative consequences, has become a major focus of addiction research. Recently, we have reported the surprising finding that both histone modifications and direct covalent modification of DNA underiy normal memory formation, as well as the maintenance of lasting memories. The goal of the current project is to study the epigenetic basis of cocaine addiction, with a specific emphasis on understanding the epigenetic mechanisms active during drug-associated memory formation and relapse to drug seeking. During the course of this project, I will investigate the hypothesis that epigenetic modifications are important for the formation, retrieval and reconsolidation of cocaine-associated memories. This will be achieved by studying the specific enzymes responsible for catalyzing histone modifications and cytosine methylation through gene expression analysis, the use of transgenic mice and intra-GNS infusions of drugs that inhibit or augment these enzymes. In addition, I will investigate the specific genes that are methylated, as well as the associated chromatin modifications using a variety of techniques, including methylation microarray, bisulfite sequencing and chromatin immunoprecipitation (ChIP). By understanding the role of the epigenome in the establishment and maintenance of drug addiction, novel sites of therapeutic intervention may be discovered.

Public Health Relevance

As drug addiction develops, addicts learn to associate the rewarding effects ofthe drug with stimuli that are present at the time of drug use. Using an animal model of addiction, this proposal explores the hypothesis that cocaine-induced modifications to an organism's epigenome are integral to the formation and expression of the aberrant memories that contribute to relapse in addicts.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Transition Award (R00)
Project #
5R00DA024761-05
Application #
8212315
Study Section
Special Emphasis Panel (NSS)
Program Officer
Satterlee, John S
Project Start
2009-12-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2013-11-30
Support Year
5
Fiscal Year
2012
Total Cost
$237,633
Indirect Cost
$91,795
Name
Scripps Florida
Department
Type
DUNS #
148230662
City
Jupiter
State
FL
Country
United States
Zip Code
33458
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Aguilar-Valles, Argel; Vaissiere, Thomas; Griggs, Erica M et al. (2014) Methamphetamine-associated memory is regulated by a writer and an eraser of permissive histone methylation. Biol Psychiatry 76:57-65
Griggs, Erica M; Young, Erica J; Rumbaugh, Gavin et al. (2013) MicroRNA-182 regulates amygdala-dependent memory formation. J Neurosci 33:1734-40
Miller, Courtney A (2011) Forgot your HAT? CBP might be to blame. Neuropsychopharmacology 36:1543-4
Rumbaugh, Gavin; Miller, Courtney A (2011) Epigenetic changes in the brain: measuring global histone modifications. Methods Mol Biol 670:263-74
Mikaelsson, Mikael A; Miller, Courtney A (2011) DNA methylation: a transcriptional mechanism co-opted by the developed mammalian brain? Epigenetics 6:548-51
Miller, Courtney A (2011) Stressed and depressed? Check your GDNF for epigenetic repression. Neuron 69:188-90
Mikaelsson, Mikael A; Miller, Courtney A (2011) The path to epigenetic treatment of memory disorders. Neurobiol Learn Mem 96:13-8
Yuskaitis, Christopher J; Mines, Marjelo A; King, Margaret K et al. (2010) Lithium ameliorates altered glycogen synthase kinase-3 and behavior in a mouse model of fragile X syndrome. Biochem Pharmacol 79:632-46
Miller, Courtney A; Gavin, Cristin F; White, Jason A et al. (2010) Cortical DNA methylation maintains remote memory. Nat Neurosci 13:664-6

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