The first round of funding was aimed at elucidating the role of H-Ras in the nucleus accumbens (NAc) in ethanol-mediated biochemical and behavioral neuroadaptations. We found that acute systemic administration of ethanol, as well excessive consumption of ethanol, results in the activation of H-Ras in the NAc of mice and rats, and that siRNA-mediated knockdown or pharmacologic inhibition of H-Ras in the NAc leads to the attenuation of ethanol-drinking behaviors in rodents. We further showed that ethanol-mediated activation of H-Ras leads to the activation of the PI3K/AKT/mTORC1 pathway in the NAc. Importantly, pharmacological inhibition of each of these kinases, including the FDA-approved mTORC1 inhibitor, Rapamycin, resulted in the inhibition of excessive ethanol consumption and seeking. Based on these results, we hypothesized that signaling pathways downstream of H-Ras in the NAc play a crucial role in the molecular mechanism underlying ethanol-drinking behaviors. Here, we plan to test whether specific pathways that stem from PI3K, AKT and mTORC1 are induced in the NAc of mice and rats in response to repeated cycles of excessive ethanol consumption and withdrawal, and whether these contribute to the development and/or maintenance of ethanol-drinking behaviors.
Aim 1 will address the role of SGK1.
In Aim 2, we will test the contribution of the transcription factor NFAc4, and the microtuble-associated protein CRMP-2 in ethanol?s actions.
In aim 3, we will identify mTORC1-dependent novel mRNAs whose translation is induced by ethanol, resulting in increased levels of proteins that control synaptic functions. HRas/ PI3K/AKT and mTORC1 inhibitors are actively being developed by the pharmaceutical industry as therapies against cancer and autoimmune diseases and as immunosuppressants. Therefore, we believe that results obtained from these experiments could further lead to the identification and rapid development of new medications to treat alcohol abuse disorders. Furthermore, the PI3K/AKTmTORC1 pathway is a focal point in various signaling cascades to be investigated within the ACTG. We will, therefore, be able to integrate our findings, share knowledge and reagents and easily collaborate on these projects.

Public Health Relevance

This proposal is aimed at studying the role of a specific signaling cascade in a brain region that is part of the reward pathway in mechanisms that underlie ethanol drinking behaviors, such as excessive consumption, seeking and relapse. Results generated from these studies can lead to the development of novel medications for alcohol addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Specialized Center (P50)
Project #
5P50AA017072-08
Application #
8794382
Study Section
Special Emphasis Panel (ZAA1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
8
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
94608
Laguesse, Sophie; Morisot, Nadege; Phamluong, Khanhky et al. (2018) mTORC2 in the dorsomedial striatum of mice contributes to alcohol-dependent F-Actin polymerization, structural modifications, and consumption. Neuropsychopharmacology 43:1539-1547
Bird, C W; Baculis, B C; Mayfield, J J et al. (2018) The brain-derived neurotrophic factor VAL68MET polymorphism modulates how developmental ethanol exposure impacts the hippocampus. Genes Brain Behav :e12484
Blasio, Angelo; Wang, Jingyi; Wang, Dan et al. (2018) Novel Small-Molecule Inhibitors of Protein Kinase C Epsilon Reduce Ethanol Consumption in Mice. Biol Psychiatry 84:193-201
Fan, Qi Wen; Nicolaides, Theodore P; Weiss, William A (2018) Inhibiting 4EBP1 in Glioblastoma. Clin Cancer Res 24:14-21
Barak, Segev; Ahmadiantehrani, Somayeh; Logrip, Marian L et al. (2018) GDNF and alcohol use disorder. Addict Biol :
Ron, Dorit; Berger, Anthony (2018) Targeting the intracellular signaling ""STOP"" and ""GO"" pathways for the treatment of alcohol use disorders. Psychopharmacology (Berl) 235:1727-1743
Blegen, Mariah B; da Silva E Silva, Daniel; Bock, Roland et al. (2018) Alcohol operant self-administration: Investigating how alcohol-seeking behaviors predict drinking in mice using two operant approaches. Alcohol 67:23-36
Vandenberg, Angela; Lin, Wan Chen; Tai, Lung-Hao et al. (2018) Mice engineered to mimic a common Val66Met polymorphism in the BDNF gene show greater sensitivity to reversal in environmental contingencies. Dev Cogn Neurosci 34:34-41
Saunders, Benjamin T; Richard, Jocelyn M; Margolis, Elyssa B et al. (2018) Dopamine neurons create Pavlovian conditioned stimuli with circuit-defined motivational properties. Nat Neurosci 21:1072-1083
Wegner, Scott A; Pollard, Katherine A; Kharazia, Viktor et al. (2017) Limited Excessive Voluntary Alcohol Drinking Leads to Liver Dysfunction in Mice. Alcohol Clin Exp Res 41:345-358

Showing the most recent 10 out of 75 publications