Alcohol use disorders (AUDS) impact millions of individuals and constitute one of the most serious public health problems worldwide. Despite its devastating impact on society, only a few effective medications are currently available. Orexins/hypocretins are hypothalamic peptides that act via orexin receptors that have been linked to regulating feeding and sleep. In addition, the orexin system has been shown to play an important role in alcohol self-administration and in stress-induced reinstatement. These effects are thought to be mediated by orexin containing neurons that project from the lateral hypothalamus to the ventral tegmental area (VTA) and nucleus accumbens (NAc) or from the perifornical regions to the amygdala respectively. However, the role of orexins through orexin receptors and their signaling pathway in driving ethanol mediated behaviors is less explored. The overall goal of this research project, component 6 of the NIAAA-Gallo Center application is to determine the role of orexins, orexin receptors and their downstream signaling pathways in different brain regions in ethanol-mediated behaviors. The Center provides a unique opportunity to apply a multidisciplinary approach that integrates behavioral, biochemical and electrophysiological techniques in the latest animal models of binge drinking, ethanol self-administration and stress-induced reinstatement.
The research aims to understand the role of orexin mediated synaptic and cellular mechanisms in the central amygdala, VTA and NAc using behavioral models of alcohol addiction.
In Aim 6. 1, we will determine whether Ox-Rs in the central amygdala drive stress-induced reinstatement of ethanol seeking.
In Aim 6. 2, we will apply electrophysiological and biochemical techniques to dissect the signaling pathways underlying orexins effects in the central amygdala.
In Aim 6. 3, we will determine the mechanism of action of orexins in the VTA and the NAc in regulating binge ethanol consumption and ethanol self-administration. Orexins/hypocretins play a crucial role in addiction, the sleep-wake cycle, motivation and stress, and this provides a strong rationale for our proposed studies, the experiments outlined have been designed specifically to lead to clinical studies aimed at determining the efficacy of orexin receptor antagonists in human subjects with AUDs.
Orexin receptors are novel therapeutic targets implicated in alcohol use disorders (AUDs) and orexin receptor antagonists are currently in Phase III clinical trials for sleep disorders. There is little known about how orexin receptors drive ethanol consumption and stress-induced reinstatement. This project provides a unique opportunity to determine the mechanism of action of orexin receptors in AUDs
|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|
|Morisot, N; Ron, D (2017) Alcohol-dependent molecular adaptations of the NMDA receptor system. Genes Brain Behav 16:139-148|
|Rinetti-Vargas, Gina; Phamluong, Khanhky; Ron, Dorit et al. (2017) Periadolescent Maturation of GABAergic Hyperpolarization at the Axon Initial Segment. Cell Rep 20:21-29|
|Liu, F; Laguesse, S; Legastelois, R et al. (2017) mTORC1-dependent translation of collapsin response mediator protein-2 drives neuroadaptations underlying excessive alcohol-drinking behaviors. Mol Psychiatry 22:89-101|
|Hopf, F W (2017) Do specific NMDA receptor subunits act as gateways for addictive behaviors? Genes Brain Behav 16:118-138|
|Blasio, Angelo; Wang, Jingyi; Wang, Dan et al. (2017) Novel Small-Molecule Inhibitors of Protein Kinase C Epsilon Reduce Ethanol Consumption in Mice. Biol Psychiatry :|
|Phamluong, Khanhky; Darcq, Emmanuel; Wu, Su et al. (2017) Fyn Signaling Is Compartmentalized to Dopamine D1 Receptor Expressing Neurons in the Dorsal Medial Striatum. Front Mol Neurosci 10:273|
|Laguesse, Sophie; Morisot, Nadege; Phamluong, Khanhky et al. (2017) Region specific activation of the AKT and mTORC1 pathway in response to excessive alcohol intake in rodents. Addict Biol 22:1856-1869|
|Fan, QiWen; Aksoy, Ozlem; Wong, Robyn A et al. (2017) A Kinase Inhibitor Targeted to mTORC1 Drives Regression in Glioblastoma. Cancer Cell 31:424-435|
|Yang, Sungchil; Ben-Shalom, Roy; Ahn, Misol et al. (2016) ?-Arrestin-Dependent Dopaminergic Regulation of Calcium Channel Activity in the Axon Initial Segment. Cell Rep 16:1518-1526|
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