? Molecular Component The TSRI-ARC as an integrated whole will focus on the neurobiology of protracted abstinence and its role in relapse and recovery. The Molecular Component will test the hypothesis that alterations in the composition and/or dynamics of the microtubule (MT) cytoskeleton contribute to the motivational and emotional symptomatology of abstinence by driving the structural remodeling of neurons in key brain regions. The first Specific Aim will be to determine alterations in MT composition and dynamics, using state-of-the-art proteomics methodology to quantify the abundance of ?- and ?-tubulin isotypes, MT-associated proteins known to regulate MT dynamics, and tubulin posttranslational modifications indicative of MT stability. These analyses will be performed in the medial prefrontal cortex (mPFC), anterior insula, and amygdala. Mice will be exposed to chronic intermittent ethanol inhalation (CIE) and brains will be collected 1 and 4 weeks into withdrawal to explore the development and persistence of molecular adaptations in early and late abstinence, respectively. The second Specific Aim will be to test the functional implication of MT alterations in ethanol drinking escalation, negative affect and dendritic remodeling during abstinence. A first approach will involve local knockdown of tubulin isotypes and MT-associated proteins to mimic or reverse abundance changes identified in Specific Aim 1. Another approach will entail systemic treatment with the synthetic pregnenolone derivative MAP4343 to stimulate MT dynamics and accelerate recovery from withdrawal. The third Specific Aim will be to complement research conducted by other TSRI-ARC components. A first experiment will probe the involvement of glucocorticoid receptor signaling in the effect of CIE on MT dynamics. A second experiment will test the role of serotonergic projections to the central amygdala and mPFC in the anxiety-like behavior associated with abstinence from CIE. Altogether, this project is anticipated to identify a molecular mechanism for the homeostatic failure?or allostasis?that characterizes alcohol use disorders and underlies relapse vulnerability during protracted abstinence. The Molecular Component will have strong interactions with the Animal Models Core, will involve collaborations with the Neurophysiology and Neurocircuitry Components, and will provide a mechanistic basis for the testing of compounds by the Clinical Component.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Comprehensive Center (P60)
Project #
2P60AA006420-35
Application #
9393656
Study Section
Special Emphasis Panel (ZAA1)
Project Start
Project End
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
35
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Mason, Barbara J; Quello, Susan; Shadan, Farhad (2018) Gabapentin for the treatment of alcohol use disorder. Expert Opin Investig Drugs 27:113-124
Varodayan, Florence P; Sidhu, Harpreet; Kreifeldt, Max et al. (2018) Morphological and functional evidence of increased excitatory signaling in the prelimbic cortex during ethanol withdrawal. Neuropharmacology 133:470-480
Matzeu, Alessandra; Martin-Fardon, Rémi (2018) Drug Seeking and Relapse: New Evidence of a Role for Orexin and Dynorphin Co-transmission in the Paraventricular Nucleus of the Thalamus. Front Neurol 9:720
Sidhu, Harpreet; Kreifeldt, Max; Contet, Candice (2018) Affective Disturbances During Withdrawal from Chronic Intermittent Ethanol Inhalation in C57BL/6J and DBA/2J Male Mice. Alcohol Clin Exp Res 42:1281-1290
Ehlers, Cindy L; Wills, Derek; Gilder, David A (2018) A history of binge drinking during adolescence is associated with poorer sleep quality in young adult Mexican Americans and American Indians. Psychopharmacology (Berl) 235:1775-1782
Pavon, Francisco J; Serrano, Antonia; Sidhpura, Nimish et al. (2018) Fatty acid amide hydrolase (FAAH) inactivation confers enhanced sensitivity to nicotine-induced dopamine release in the mouse nucleus accumbens. Addict Biol 23:723-734
Logrip, Marian L; Walker, John R; Ayanwuyi, Lydia O et al. (2018) Evaluation of Alcohol Preference and Drinking in msP Rats Bearing a Crhr1 Promoter Polymorphism. Front Psychiatry 9:28
Serrano, Antonia; Pavon, Francisco J; Buczynski, Matthew W et al. (2018) Deficient endocannabinoid signaling in the central amygdala contributes to alcohol dependence-related anxiety-like behavior and excessive alcohol intake. Neuropsychopharmacology 43:1840-1850
Spierling, Samantha R; Kreisler, Alison D; Williams, Casey A et al. (2018) Intermittent, extended access to preferred food leads to escalated food reinforcement and cyclic whole-body metabolism in rats: Sex differences and individual vulnerability. Physiol Behav 192:3-16
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

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