We have made significant progress, through support from this RO1/R37 grant, in identifying adaptations in signal transduction proteins induced in the mesolimbic dopamine system by chronic exposure to cocaine or other drugs of abuse. This neural system, which consists of dopaminergic neurons in the ventral tegmental area (VTA) and their projection regions such as the nucleus accumbens (NAc), is implicated in the reinforcing and addicting actions of these drugs. Work over the past 5 years has focused largely on two transcription factors, deltaFosB and CREB, as important mediators of the longer-lasting effects of drugs on the VTA-NAc pathway. CREB activation by drugs of abuse, which is relatively short-lived after cessation of drug use, appears to represent a mechanism of drug tolerance and dependence, and could mediate a negative emotional state seen in many addicts during early phases of drug withdrawal. The situation for deltaFosB is very different. deltaFosB, like CREB, is induced in the NAc and certain other regions by chronic exposure to drugs of abuse, however, unlike CREB, deltaFosB is long-lived in that it persists in brain for as long as 6-8 weeks after cessation of drug administration. Also unlike CREB, deltaFosB appears to mediate enhanced sensitivity to the rewarding effects of drugs of abuse. Thus, deltaFosB could represent a mechanism of relatively prolonged sensitization that contributes to features of addiction long after the last drug exposure. In formulating a plan for this competitive renewal of this R01 grant, we have decided to focus our efforts on characterizing the deltaFosB system in greater detail. (Our studies of CREB will continue with support from other grants.) Our focus on deltaFosB is justified by several considerations. First, deltaFosB is induced by virtually all drugs of abuse in the NAc and certain other regions, but there has to date been no systematic characterization of precisely where such induction occurs in brain and in which cell type. Second, deltaFosB's unusual stability provides a novel potential mechanism underlying some of the long-term effects of drugs of abuse on the brain. Yet, there has been no information available as to the biochemical mechanisms responsible for this stability. Third, virtually nothing is known about regulation of the fosB gene, the induction of which is also required for deltaFosB accumulation with drugs of abuse. Fourth, as a transcription factor, deltaFosB's interesting effects on behavior are presumably mediated via alterations in the expression of target genes, but the regulation of gene expression by deltaFosB in the NAc and other brain regions in vivo remains incompletely understood. The goal of the proposed studies, then, is to make significant progress in these several critical areas of investigation: to better understand, at the precise molecular level, exactly how and where deltaFosB is induced by chronic drug exposure, why deltaFosB persists in brain for so long, and the target genes through which deltaFosB mediates aspects of the drug-addicted phenotype. This work will contribute to our growing knowledge of drug-induced neuroadaptations in the brain at the molecular level. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA007359-18
Application #
7231714
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Pollock, Jonathan D
Project Start
1991-08-01
Project End
2011-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
18
Fiscal Year
2007
Total Cost
$399,573
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Psychiatry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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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
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

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