We are requesting funds for the competitive renewal of our Program Project Grant (PPG) from NIDA, entitled Molecular Neurobiology of Drug Addiction. The PPG supports a series of highly interactive and multidisciplinary studies aimed at delineating the molecular and cellular mechanisms underlying opiate and cocaine addiction. Each research area represents an integration of molecular, biochemical, electrophysiological, neuropharmacological, neuroanatomical, and behavioral levels of analysis, which are focused very tightly around the roles played by two transcription factors, CREB and ?FosB, and a small number of their putative target genes, in the brain's reward pathways in opiate and cocaine action. The PPG is organized into a small Administrative Core, two scientific Cores, and four Projects. The Transgenic Core (PI, Eric Nestler) is responsible for breeding the many lines of transgenic and knockout mice, and for constructs for viral-mediated gene transfer, to be utilized in the proposed research. The Core is also responsible for the construction of several new lines of mutant mice, including those with inducible tissue-specific transgenes and knockouts. The Behavioral Core (PI, David Self) is responsible for providing to individual Projects a broad battery of behavioral tests in mice and rats relevant to drug abuse and addiction. The capacity of the Core is expanded through a subcontract with Jane Taylor at Yale. Project 1 (PI, Eric Nestler) is a continuation of a productive and collaborative effort among several laboratories to study the role of CREB in the mesolimbic dopamine reward circuit, comprised of dopamine neurons in the ventral tegmental area (VTA) and their projection regions, in particular, the nucleus accumbens (NAc). A substantial body of evidence supports our hypothesis that opiate and cocaine induction of CREB activity in these regions is an important mediator of long-term drug effects in both of these brain reward regions. Project 2 (PI, Rob Malenka via a Stanford subcontract) focuses on characterizing the functional consequences of specific drug-induced molecular adaptations in the mesolimbic dopamine system in neurophysiology and synaptic plasticity models. The Project concentrates on the cellular actions of CREB and ?FosB and a small number of putative target genes in the NAc. Project 3 (PI, Eric Nester) is a new effort, which consolidates the PPG's investigations of mechanisms of gene regulation in the VTA-NAc in response to chronic opiate or cocaine administration, with a particular focus on the role played by CREB and ?FosB. A major aspect of the Project's research is drug regulation of chromatin remodeling mechanisms, which have provided novel insight into the long-lasting effects of the drugs on gene regulation. Project 4 (PI, David Self) is a continuation of efforts to study the role of drug-induced molecular adaptations in the mesolimbic dopamine system in animal models of drug reinforcement and craving. Project investigators focus on the behavioral phenotype induced by CREB and ?FosB, and a small number of putative target genes, within this reward circuit. Together, the proposed program of research is tightly focused on transcriptional mechanisms in drug action, and will continue to contribute to a better understanding of drug addiction at the molecular, cellular, and systems levels. PROGRAM PROJECT CHARACTERISTICS

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Program Projects (P01)
Project #
3P01DA008227-21S1
Application #
8684698
Study Section
Special Emphasis Panel (ZDA1-RXL-E (11))
Program Officer
Pollock, Jonathan D
Project Start
1997-08-01
Project End
2013-12-30
Budget Start
2013-07-01
Budget End
2013-12-30
Support Year
21
Fiscal Year
2013
Total Cost
$806,361
Indirect Cost
$197,529
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
Hamilton, Peter J; Lim, Carissa J; Nestler, Eric J et al. (2018) Stereotaxic Surgery and Viral Delivery of Zinc-Finger Epigenetic Editing Tools in Rodent Brain. Methods Mol Biol 1867:229-238
Inquimbert, Perrine; Moll, Martin; Latremoliere, Alban et al. (2018) NMDA Receptor Activation Underlies the Loss of Spinal Dorsal Horn Neurons and the Transition to Persistent Pain after Peripheral Nerve Injury. Cell Rep 23:2678-2689
Ayata, Pinar; Badimon, Ana; Strasburger, Hayley J et al. (2018) Epigenetic regulation of brain region-specific microglia clearance activity. Nat Neurosci 21:1049-1060
Walker, Deena M; Nestler, Eric J (2018) Neuroepigenetics and addiction. Handb Clin Neurol 148:747-765
Li, Xuan; Carreria, Maria B; Witonsky, Kailyn R et al. (2018) Role of Dorsal Striatum Histone Deacetylase 5 in Incubation of Methamphetamine Craving. Biol Psychiatry 84:213-222
Anderson, Ethan M; Larson, Erin B; Guzman, Daniel et al. (2018) Overexpression of the Histone Dimethyltransferase G9a in Nucleus Accumbens Shell Increases Cocaine Self-Administration, Stress-Induced Reinstatement, and Anxiety. J Neurosci 38:803-813
Walker, Deena M; Cates, Hannah M; Loh, Yong-Hwee E et al. (2018) Cocaine Self-administration Alters Transcriptome-wide Responses in the Brain's Reward Circuitry. Biol Psychiatry 84:867-880
Cahill, Michael E; Browne, Caleb J; Wang, Junshi et al. (2018) Withdrawal from repeated morphine administration augments expression of the RhoA network in the nucleus accumbens to control synaptic structure. J Neurochem 147:84-98
Cates, Hannah M; Li, Xuan; Purushothaman, Immanuel et al. (2018) Genome-wide transcriptional profiling of central amygdala and orbitofrontal cortex during incubation of methamphetamine craving. Neuropsychopharmacology 43:2426-2434
Gaspari, Sevasti; Purushothaman, Immanuel; Cogliani, Valeria et al. (2018) Suppression of RGSz1 function optimizes the actions of opioid analgesics by mechanisms that involve the Wnt/?-catenin pathway. Proc Natl Acad Sci U S A 115:E2085-E2094

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