The overall objectives of this U01 research core application are to (a) provide selectively bred high ethanol (EtOH)-consuming rats that have experienced the drinking-in-dark (DID) EtOH binge-drinking protocol and their controls, or whole brains or brain sub-regions from these rats;and (b) use shRNAi's and other pharmacological tools to help identify genes, gene systems and receptors involved in the predisposition for, and development and maintenance of, EtOH binge-drinking. The overall hypothesis is that particular 'candidate'genes and their associated molecular networks within the extended amygdala and associated brain regions significantly contribute to the development and maintenance of, and a predisposition for, excessive EtOH drinking. The overall hypothesis will be tested by (a) providing alcohol-preferring (P) and high-alcohol-drinking (HAD) rats (or their whole brains or brain regions) that have been taken through the binge drinking protocol to other INIA U01 investigators;(b) using shRNAi's to reduce expression of 'candidate'genes within the extended amygdala and associated regions;and (c) examining the effects of ligands targeted for 'candidate'gene products and their molecular networks on, binge-drinking. Providing insight into the complex molecular and cellular events that lead to the development and maintenance of excessive alcohol drinking behavior in animal models is highly significant since these findings will provide the necessary foundation for developing novel treatment strategies targeting alcohol abuse and alcoholism. This is a highly innovative project since it will use state-of-the-art techniques to selectively reduce expression of 'candidate'genes in multiple genetically predisposed 'families'(i.e., the P, HAD1 and HAD2) of rats and in discrete CNS regions that are involved in regulating alcohol drinking. This U01 research core provides synergy with several INIA-West components by addressing the first two specific aims of INIA, i.e., confirm gene targets and identify drugable targets for medications focused on treating alcohol abuse and alcoholism.
Alcohol abuse, alcoholism and their consequences continue to be the third leading cause of death in the U.S. Moreover, alcohol binge-drinking among today's youth and young adults is a major public health concern. Understanding the molecular neurobiological events mediating alcohol abuse or a genetic predisposition for this behavior continues to aid in the development of treatments for alcohol use disorders.
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|McClintick, Jeanette N; McBride, William J; Bell, Richard L et al. (2018) Gene expression changes in the ventral hippocampus and medial prefrontal cortex of adolescent alcohol-preferring (P) rats following binge-like alcohol drinking. Alcohol 68:37-47|
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|Harris, R Adron; Bajo, Michal; Bell, Richard L et al. (2017) Genetic and Pharmacologic Manipulation of TLR4 Has Minimal Impact on Ethanol Consumption in Rodents. J Neurosci 37:1139-1155|
|Mittal, N; Thakore, N; Bell, R L et al. (2017) Sex-specific ultrasonic vocalization patterns and alcohol consumption in high alcohol-drinking (HAD-1) rats. Physiol Behav :|
|Dir, Allyson L; Bell, Richard L; Adams, Zachary W et al. (2017) Gender Differences in Risk Factors for Adolescent Binge Drinking and Implications for Intervention and Prevention. Front Psychiatry 8:289|
|Bell, Richard L; Hauser, Sheketha R; McClintick, Jeanette et al. (2016) Ethanol-Associated Changes in Glutamate Reward Neurocircuitry: A Minireview of Clinical and Preclinical Genetic Findings. Prog Mol Biol Transl Sci 137:41-85|
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