Thursday, April 25, 2024
4/25/2024
Abstract Overall The Alcohol Research Center of The Scripps Research Institute (TSRI-ARC) proposes to continue its interdisciplinary program focused on the theme of the central nervous system effects of alcohol. For this renewal application, the TSRI-ARC (P60) will consist of 9 components, including 3 Cores (Administrative, Animal Models and Information Dissemination) and 5 Research Projects (Molecular, Neurophysiology, Neurocircuitry, Neurochemistry, and Clinical). The overall hypothesis of the TSRI-ARC as an integrated whole is that the central stress systems become activated during the withdrawal/negative affect stage and persist into protracted abstinence (in the preoccupation/anticipation stage), and such neuroadaptive changes associated with chronic drinking also produce an evolving set of neurobehavioral symptoms that include hypohedonia, anxiety, irritability, negative affect, hyperarousal, and sleep disturbances, all of which contribute to relapse and impede recovery. The specific subhypotheses are: 1) The transition from acute withdrawal to protracted abstinence includes compulsive-like responding for ethanol and negative emotional behavior that involves changes in interconnected brain areas: the extended amygdala, the medial prefrontal cortex, and the anterior insula. 2) The altered activity in these circuits reflects actions of stress-related system including glucocorticoids, serotonin, hypocretin, and corticotropin-releasing factor. 3) Cellular neuroadaptations are associated with altered dynamics of the microtubule cytoskeleton, which may in turn mediate the structural remodeling of neuronal dendrites. 4) Novel neurobiological targets identified by the TSRI-ARC will significantly attenuate the reinstatement of compulsive-like alcohol seeking, excessive drinking, and anxiety-like behavior;; and 5) drug candidates for these targets will be active in a human lab model of protracted abstinence where they will reduce drinking, craving, negative affect, and executive function deficits. We believe the proposed innovative approaches for testing these hypotheses will provide valuable insight into novel approaches for treating alcoholism and relapse in the humans. The TSRI-ARC also supports the Center at Large, which includes: 31 R01s, 10 R21s, 3 U01s, 1 U24, 2 R37s, 2 R13s, and one T32 NIAAA training grant associated with this grant. Members of the Center at Large have access to the Cores of the TSRI-ARC, the NIAAA Integrative Neuroscience Initiative on Alcoholism (INIA) Consortia. Training and information dissemination to the San Diego community will be effected by the training opportunities of the Center including a T32 NIAAA training grant and the Information Dissemination Core.
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