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 will be a P60 consisting of 9 components plus an Educational Component. Four core components are proposed: Administrative, Animal Models/Biochemical Measures, Biochemical and Pilot. Five research components are proposed: Cellular Electrophysiology, Cellular Physiology, Neuroendocrinology, Neurochemistry, and Clinical Neurobehavioral. The overall hypothesis of the TSRI-ARC is that with chronic binge drinking, the brain """"""""reward"""""""" systems become tolerant to alcohol while central stress systems become activated and that as a result, the neuroadaptive changes associated with chronic drinking produce an evolving set of neurobehavioral symptoms that include hypohedonia, anxiety, hyperarousal, sleep disturbances, and negative affect, conceptualized as the """"""""dark side"""""""" of addiction. The subhypotheses for the present proposal are: (1) The transition from low levels of drinking (1-2 drinks within 2 hours in humans) to chronic binge drinking (4-5 drinks within 2 hours in humans) is driven by decreased activity of opioid peptide systems and endocannabinoid systems in """"""""reward circuits"""""""" in the frontal cortex, and nucleus accumbens (Specific Aim 1). (2) The transition from binge drinking to dependence is driven by compromised function in the reward systems and recruitment of a dysregulated central stress system, most notably driven by changes in CRF, glutamate, and endocannabinoids in the extended amygdala (Specific Aim 2). (3) A particularly vulnerable local human clinical population has a phenotype of alcoholism that displays this transition from bingeing to dependence in young adulthood, allowing us to translate our findings in animals to humans and humans to animals (Specific Aim 3). We believe the proposed innovative approaches for testing these hypotheses will provide valuable insight into novel approaches for treating and preventing alcoholism in the human population. The TSRI-ARC also supports the Center at Large, which includes: 13 ROIs, 6 UOIs, one T32 NIAAA training grant, two R37s, one R13, one RC1 award. Members of the Center at Large have access to the Cores of the TSRI-ARC, the INIA Cores and the TSRI NIAAA Training Grant in Neuropsychopharmacology. Training and information dissemination to the San Diego community will be effected by the training opportunities of the Center including an NIAAA training grant and the Education Component.

Public Health Relevance

This Center proposes to continue its interdisciplinary program focused on the theme of the central nervous system's effects of alcohol. A particularly vulnerable local human clinical population has a phenotype of alcoholism that displays a transition from bingeing to dependence in young adulthood, allowing us to translate our findings in animals to humans and humans to animals. We believe this project will provide valuable insight into novel approaches for treating and preventing alcoholism in the human population.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Comprehensive Center (P60)
Project #
5P60AA006420-31
Application #
8616698
Study Section
Special Emphasis Panel (ZAA1-GG (50))
Program Officer
Egli, Mark
Project Start
1983-12-01
Project End
2017-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
31
Fiscal Year
2014
Total Cost
$1,608,165
Indirect Cost
$759,529
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Schmeichel, Brooke E; Matzeu, Alessandra; Koebel, Pascale et al. (2018) Knockdown of hypocretin attenuates extended access of cocaine self-administration in rats. Neuropsychopharmacology 43:2373-2382
Kononoff, Jenni; Kallupi, Marsida; Kimbrough, Adam et al. (2018) Systemic and Intra-Habenular Activation of the Orphan G Protein-Coupled Receptor GPR139 Decreases Compulsive-Like Alcohol Drinking and Hyperalgesia in Alcohol-Dependent Rats. eNeuro 5:
Kreisler, A D; Mattock, M; Zorrilla, E P (2018) The duration of intermittent access to preferred sucrose-rich food affects binge-like intake, fat accumulation, and fasting glucose in male rats. Appetite 130:59-69
Varodayan, F P; Khom, S; Patel, R R et al. (2018) Role of TLR4 in the Modulation of Central Amygdala GABA Transmission by CRF Following Restraint Stress. Alcohol Alcohol 53:642-649
McClatchy, Daniel B; Yu, Nam-Kyung; Martínez-Bartolomé, Salvador et al. (2018) Structural Analysis of Hippocampal Kinase Signal Transduction. ACS Chem Neurosci :
Berger, Anthony L; Henricks, Angela M; Lugo, Janelle M et al. (2018) The Lateral Habenula Directs Coping Styles Under Conditions of Stress via Recruitment of the Endocannabinoid System. Biol Psychiatry 84:611-623
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

Showing the most recent 10 out of 211 publications