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
|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|
|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|
|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