Cocaine abuse is a significant public health problem, with approximately 1.4 million Americans meeting the DSMIV criteria for cocaine dependence and acute overdoses causing nearly 500,000 emergency room visits each year. In spite of this, there are remarkably few effective treatments for cocaine addiction and abuse. Part of the difficulty in the medical treatment of cocaine addiction is that even after successful short-term treatment, environmental cues can evoke craving and drug relapse. Behavioral and neurobiological approaches to memory have identified extinction, in which the relation between the cue and the drug is severed, as a way to eliminate conditioned behavior. A challenge for extinction-based therapies, however, is that extinguished behavior often returns with time or after re-exposure to the drug. In our initial period of support, we examined pharmacological approaches that, when paired with behavioral extinction, generated a rapid and persistent loss of drug-seeking that was resistant to reinstatement challenges (relapse-like behavior). Our focus has been on the regulation of gene expression necessary for long-term memory formation, which involves the concerted action of multiple transcription factors and cofactors that interact with chromatin, a protein complex that packages DNA. Chromatin modification is a main mechanism of epigenetic gene regulation, which is emerging as a major molecular pathway involved in synaptic plasticity and memory storage. Epigenetic gene regulation has been shown to underlie persistent long-term changes at the cellular level as well as the behavioral level. Importantly, in animal models of addiction, chronic drug exposure induces stable chromatin modification resulting in stable synaptic plasticity changes, which is thought to drive persistnt changes in behavior. Considering the substantial overlap in the circuitry involved in drug addiction and learning and memory pathways, the focus of this grant proposal is to modulate learning and memory pathways in order to extinguish drug associated memories. In this renewal application, we focus on a specific mechanism of regulating histone acetylation via histone deacetylase 3 (HDAC3). We use genetic, viral, and pharmacological manipulations to investigate the role of HDAC3 in extinction of cocaine-induced conditioned place preferences and intravenous cocaine self-administration. We hypothesize that HDAC3 is a key negative regulator of extinction of drug-seeking behavior and that HDAC3 modulates extinction via regulation of Nr4a (nuclear orphan receptor) gene family.
In Specific Aim 1, we will use a novel pharmacological approach to determine the role of HDAC3 specifically in memory consolidation during extinction.
In Specific Aim 2, we will use a genetic and viral approach to determine the role of long-term modulation of HDAC3 in extinction.
In Specific Aim 3, we will use a molecular approach to determine the role of the Nr4a gene family (HDAC3 target genes) in extinction. Our approach promises to elucidate behavioral, systems, and epigenetic mechanisms of extinction and elucidate novel molecular targets for pharmacological interventions.

Public Health Relevance

Cocaine addiction is a major public health problem in the United States. There are no FDA approved medications for cocaine addiction, but epigenetic mechanisms hold great promise because they result in stable, long-term changes in cell function that ultimately establish stable behavior. In this proposal, we will examine a very specific epigenetic mechanism (modulation of histone deacetylase 3) that, when paired with behavioral treatments in a rodent model, may help reverse cocaine seeking and reduce relapse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA025922-06A1
Application #
8636891
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Satterlee, John S
Project Start
2008-09-15
Project End
2019-02-28
Budget Start
2014-03-15
Budget End
2015-02-28
Support Year
6
Fiscal Year
2014
Total Cost
$534,209
Indirect Cost
$97,352
Name
Oregon Health and Science University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Hitchcock, Leah N; Cunningham, Christopher L; Lattal, K Matthew (2014) Cue configuration effects in acquisition and extinction of a cocaine-induced place preference. Behav Neurosci 128:217-27
Delamater, Andrew R; Lattal, K Matthew (2014) The study of associative learning: mapping from psychological to neural levels of analysis. Neurobiol Learn Mem 108:1-4
Raybuck, J D; Lattal, K M (2014) Differential effects of dorsal hippocampal inactivation on expression of recent and remote drug and fear memory. Neurosci Lett 569:1-5
Bolkan, Scott S; Lattal, K Matthew (2014) Opposing effects of D-cycloserine on fear despite a common extinction duration: interactions between brain regions and behavior. Neurobiol Learn Mem 113:25-34
Kwapis, Janine L; Wood, Marcelo A (2014) Epigenetic mechanisms in fear conditioning: implications for treating post-traumatic stress disorder. Trends Neurosci 37:706-20
Tipps, Megan E; Raybuck, Jonathan D; Lattal, K Matthew (2014) Substance abuse, memory, and post-traumatic stress disorder. Neurobiol Learn Mem 112:87-100
Abraham, Antony D; Neve, Kim A; Lattal, K Matthew (2014) Dopamine and extinction: a convergence of theory with fear and reward circuitry. Neurobiol Learn Mem 108:65-77
Raybuck, Jonathan D; Lattal, K Matthew (2014) Bridging the interval: theory and neurobiology of trace conditioning. Behav Processes 101:103-11
White, Andre O; Wood, Marcelo A (2014) Does stress remove the HDAC brakes for the formation and persistence of long-term memory? Neurobiol Learn Mem 112:61-7
Vogel-Ciernia, Annie; Wood, Marcelo A (2014) Examining object location and object recognition memory in mice. Curr Protoc Neurosci 69:8.31.1-8.31.17

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