The major goal of this P01 is to leverage institutional strengths in human, non-human primate, and rodent alcohol research to conduct translational studies directed at understanding the complex relationships between early life stress and vulnerability to alcohol use disorders. This project will take advantage of a highly productive and successful translational alcohol research unit at WFHS that was recently established with NIAAA programmatic grant support. This research unit will employ multidisciplinary approaches to identify enduring behavioral and neurobiological consequences of early life stress, determine how these alterations contribute to excessive alcohol drinking behaviors, and test novel interventional strategies that may be effective at alleviating addiction vulnerability associated with early life stress. The overarching hypothesis is that early life stress results in long lastin behavioral alterations that contribute to an increased risk of alcohol addiction (with a focus on anxiety-like behaviors). It is also hypothesized that these behavioral alterations are mediated, in part, by dysregulatlon of dopamine signaling and glutamate receptor function and plasticity in the nucleus accumbens. Aspects of these hypotheses will be evaluated in human subjects with and without a history of early life stress and with well-established non-human primate and rodent models of early life stress. This P01 will employ a Center-like structure that will include highly integrated rodent, non-human primate, and human projects. An administrative core will provide the infrastructure and support needed to ensure the success of the research. This core will also actively promote new translational alcohol research through a pilot project program and create new translational research training and outreach activities related to the scientific goals f the P01. A major emphasis will be to promote scientific integration across projects to maximize the likelihood of proceeding from benchside discovery to novel treatment strategies for alcohol addiction.
The proposed studies outline a multidisciplinary, translational research initiative that will bring together human, non-human primate, and rodent alcohol researchers to address complex and unresolved questions regarding the neurobiological mechanisms that link early life stress and alcohol addiction. These translational studies will shed new light on important behavioral phenotypes associated with early environmental stress, their association with excessive alcohol drinking, and specific neurobiological mechanisms that may underlie these relationships. This project will also explore novel interventional strategies that may mitigate the increased addiction vulnerability associated with early-life stress.
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|Karkhanis, Anushree N; Huggins, Kimberly N; Rose, Jamie H et al. (2016) Switch from excitatory to inhibitory actions of ethanol on dopamine levels after chronic exposure: Role of kappa opioid receptors. Neuropharmacology 110:190-7|
|Brust, Tarsis F; Morgenweck, Jenny; Kim, Susy A et al. (2016) Biased agonists of the kappa opioid receptor suppress pain and itch without causing sedation or dysphoria. Sci Signal 9:ra117|
|Rose, Jamie H; Karkhanis, Anushree N; Steiniger-Brach, BjÃ¶rn et al. (2016) Distinct Effects of Nalmefene on Dopamine Uptake Rates and Kappa Opioid Receptor Activity in the Nucleus Accumbens Following Chronic Intermittent Ethanol Exposure. Int J Mol Sci 17:|
|Karkhanis, Anushree N; Rose, Jamie H; Weiner, Jeffrey L et al. (2016) Early-Life Social Isolation Stress Increases Kappa Opioid Receptor Responsiveness and Downregulates the Dopamine System. Neuropsychopharmacology 41:2263-74|
|Yorgason, Jordan T; Calipari, Erin S; Ferris, Mark J et al. (2016) Social isolation rearing increases dopamine uptake and psychostimulant potency in the striatum. Neuropharmacology 101:471-9|
|Fordahl, Steve C; Jones, Sara R (2016) High Fat Diet-Induced Deficits in Dopamine Terminal Function are Reversed by Restoring Insulin Signaling. ACS Chem Neurosci :|
|Siciliano, Cody A; Calipari, Erin S; Yorgason, Jordan T et al. (2016) Chronic ethanol self-administration in macaques shifts dopamine feedback inhibition to predominantly D2 receptors in nucleus accumbens core. Drug Alcohol Depend 158:159-63|
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