This R01 grant is aimed at better understanding the molecular mechanisms by which chronic exposure to drugs of abuse induces long-lasting changes in the brain's reward circuits that contribute to the complex behavioral abnormalities that define an addicted state. Our work focuses on the transcription factor, FosB, which is induced in the nucleus accumbens (NAc) and other key brain reward regions in response to chronic administration of virtually all drugs of abuse. FosB is unique in that it accumulates to appreciable levels only after chronic drug exposure and, because of its unusual stability, persists for weeks-months of withdrawal. FosB is thus one mechanism by which chronic drug exposure can drive long-lasting changes in gene expression that contribute to addiction. Indeed, considerable evidence supports the view that induction of FosB in NAc mediates a state of heightened reward and motivation that could contribute to aspects of the addiction process. In this competitive renewal, we will characterize the precise mechanisms through which FosB exerts these actions. Using state-of-the-art genome-wide chromatin assays, we will identify the genes in the NAc that are direct targets for FosB in the context of cocaine and opiate administration. Such genes, in turn, provide novel insight into the molecular and cellular basis of drug-induced neural and behavioral plasticity. Interestingly, when FosB binds to its target genes, it can either activate or repress them. Our hypothesis is that such activation vs. repressive actions are determined by the chromatin milieu of the affected gene. As well, despite the fact that cocaine and opiates induce FosB in the same subtype of NAc neuron, partially non-overlapping genes are regulated by FosB in response to the two drugs. Once again, our hypothesis is that this specificity is mediated by differences in other chromatin changes that cocaine and opiates induce at specific genes. In addition to exploring FosB's regulation of target genes, we will also characterize several mechanisms that are crucial in determining the amount and activity of FosB induced in the NAc. Together, these studies will identify many novel actions of drugs of abuse which can be exploited for the development of improved diagnostic tests and treatments for addiction.

Public Health Relevance

We believe that the best way to ultimately develop improved diagnostic tests and treatments for drug addiction is through a better understanding of the basic biological mechanisms involved. This R01 grant renewal will contribute importantly to this goal by defining many novel genes and proteins, and therefore novel biochemical pathways and neural mechanisms, involved in the addiction process.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA007359-23
Application #
8107123
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Pollock, Jonathan D
Project Start
1991-08-01
Project End
2016-03-31
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
23
Fiscal Year
2011
Total Cost
$534,989
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Neurosciences
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Sun, HaoSheng; Damez-Werno, Diane M; Scobie, Kimberly N et al. (2017) Regulation of BAZ1A and nucleosome positioning in the nucleus accumbens in response to cocaine. Neuroscience 353:1-6
Walker, Deena M; Bell, Margaret R; Flores, Cecilia et al. (2017) Adolescence and Reward: Making Sense of Neural and Behavioral Changes Amid the Chaos. J Neurosci 37:10855-10866
Engmann, Olivia; Labonté, Benoit; Mitchell, Amanda et al. (2017) Cocaine-Induced Chromatin Modifications Associate With Increased Expression and Three-Dimensional Looping of Auts2. Biol Psychiatry 82:794-805
Kiraly, Drew D; Walker, Deena M; Calipari, Erin S et al. (2016) Alterations of the Host Microbiome Affect Behavioral Responses to Cocaine. Sci Rep 6:35455
Heller, Elizabeth A; Hamilton, Peter J; Burek, Dominika D et al. (2016) Targeted Epigenetic Remodeling of the Cdk5 Gene in Nucleus Accumbens Regulates Cocaine- and Stress-Evoked Behavior. J Neurosci 36:4690-7
McHenry, Jenna A; Robison, Christopher L; Bell, Genevieve A et al. (2016) The role of ?fosB in the medial preoptic area: Differential effects of mating and cocaine history. Behav Neurosci 130:469-78
Nestler, Eric J (2016) Reflections on: ""A general role for adaptations in G-Proteins and the cyclic AMP system in mediating the chronic actions of morphine and cocaine on neuronal function"". Brain Res 1645:71-4
Nestler, Eric J; Peña, Catherine J; Kundakovic, Marija et al. (2016) Epigenetic Basis of Mental Illness. Neuroscientist 22:447-63
Kim, Hee-Dae; Hesterman, Jennifer; Call, Tanessa et al. (2016) SIRT1 Mediates Depression-Like Behaviors in the Nucleus Accumbens. J Neurosci 36:8441-52
Ohnishi, Y N; Ohnishi, Y H; Vialou, V et al. (2015) Functional role of the N-terminal domain of ?FosB in response to stress and drugs of abuse. Neuroscience 284:165-70

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