The Alcohol Center for Translational Genetics (ACTG) will identify novel proteins as targets for therapeutics for alcohol use disorders and will determine mechanisms by which they act to regulate excessive ethanol intake. Candidate proteins will be evaluated in ethanol self-administration procedures that model excessive binge drinking in humans, motivation to drink ethanol, and relapse. The anatomical focus will be on 3 brain regions, the nucleus accumbens, the amygdala, and the ventral tegmental area, which all play important roles in ethanol consumption and relapse. Based on findings during the current funding cycle that identified H-Ras/PI3 kinaseAKT/mTORC1 signaling as a key regulator of ethanol consumption, all Research Components will include experiments that test the relationship of the novel proteins with this pathway. Three research projects will focus on proteins new to alcohol research: SGK1, GSK-3 and others whose translation is regulated by mTORC1 (Component 4);PKM? and its direct substrates (Component 5);and orexin/hypocretin receptors (Component 6). An Administrative Core (Component 1) will manage ACTG functions. An Animal Behavior Core (Component 2) will perform studies of intermittent ethanol access in rats and mice and will provide assistance in rat operant self-administration procedures. A Vector and Imaging Core (Component 3) will provide state-of-the art services to generate viral vectors for transgenic expression or gene silencing, and to analyze transcript and protein abundance by laser capture microdissection, high resolution immunofluorescence, and quantitative fluorescent in situ hybridization for detecting mRNAs in dendrites. Two Pilot projects are planned. The first will test the hypothesis that delta opioid receptor mediated inhibition of GABA release decreases alcohol consumption in anxious alcoholics. The second will determine whether up-regulation of NMDA receptor activity, induced by excessive ethanol consumption, facilitates long-term potentiation in the dorsomedial striatum, and thereby enhances ethanol drinking and seeking. Collectively, the ACTG provides a unique opportunity for integrated study of novel proteins that may lead to the development of new treatments for alcohol use disorders in humans.

Public Health Relevance

The ACTG is an NIAAA-funded research center dedicated to the study of proteins, not studied previously by others in the alcohol research community, that regulate high levels of ethanol consumption in rats and mice. The overall goal of the ACTG is to determine if these novel proteins could be useful as targets for developing drugs to treat people who drink alcohol excessively.

Agency
National Institute of Health (NIH)
Type
Specialized Center (P50)
Project #
5P50AA017072-08
Application #
8687559
Study Section
Special Emphasis Panel (ZAA1)
Program Officer
Reilly, Matthew
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Neurology
Type
Schools of Medicine
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
94143
King, Ian F G; Eddison, Mark; Kaun, Karla R et al. (2014) EGFR and FGFR pathways have distinct roles in Drosophila mushroom body development and ethanol-induced behavior. PLoS One 9:e87714
Trudell, James R; Messing, Robert O; Mayfield, Jody et al. (2014) Alcohol dependence: molecular and behavioral evidence. Trends Pharmacol Sci 35:317-23
Darcq, Emmanuel; Hamida, Sami Ben; Wu, Su et al. (2014) Inhibition of striatal-enriched tyrosine phosphatase 61 in the dorsomedial striatum is sufficient to increased ethanol consumption. J Neurochem 129:1024-34
Lee, Anna M; Zou, Mimi E; Lim, Jana P et al. (2014) Deletion of Prkcz increases intermittent ethanol consumption in mice. Alcohol Clin Exp Res 38:170-8
Becker, Howard C; Ron, Dorit (2014) Animal models of excessive alcohol consumption: recent advances and future challenges. Alcohol 48:205-8
Neasta, Jeremie; Barak, Segev; Hamida, Sami Ben et al. (2014) mTOR complex 1: a key player in neuroadaptations induced by drugs of abuse. J Neurochem 130:172-84
Steinberg, Elizabeth E; Boivin, Josiah R; Saunders, Benjamin T et al. (2014) Positive reinforcement mediated by midbrain dopamine neurons requires D1 and D2 receptor activation in the nucleus accumbens. PLoS One 9:e94771
Carnicella, Sebastien; Ron, Dorit; Barak, Segev (2014) Intermittent ethanol access schedule in rats as a preclinical model of alcohol abuse. Alcohol 48:243-52
Ben Hamida, Sami; Darcq, Emmanuel; Wang, Jun et al. (2013) Protein tyrosine phosphatase * in the dorsomedial striatum promotes excessive ethanol-drinking behaviors. J Neurosci 33:14369-78
Barak, Segev; Liu, Feng; Ben Hamida, Sami et al. (2013) Disruption of alcohol-related memories by mTORC1 inhibition prevents relapse. Nat Neurosci 16:1111-7

Showing the most recent 10 out of 31 publications