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.
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.
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