Alcoholism is a chronic, relapsing disorder, characterized by withdrawal syndromes of negative emotional symptoms that putatively promote relapse via negative reinforcement mechanisms. The present application tests the overarching hypothesis that excitatory glutamatergic signaling in the amygdala is altered during ethanol withdrawal, partly due to actions of corticotropin-releasing factor systems and neuronal pentraxin 2, and thereby promote negative emotional symptoms and relapse risk during abstinence. To test this hypothesis, SPECIFIC AIM 1 will use site-specific administration of recently available, highly available classand subunit selective antagonists of ionotropic glutamate receptors to test their functional involvement in the increased anxiety-like behavior and ethanol self-administration of alcohol withdrawal.
SPECIFIC AIM 2 will use glutamate system-restricted knockdown of CRF1 signaling to test the hypothesis that CRF1-driven increases in glutamatergic signaling originating from the BLA promotes anxiety-like behavior and ethanol self-administration during withdrawal from chronic intermittent ethanol exposure. Finally, SPECIFIC AIM 3 will use dominant negative Narp-mediated knockdown of Narp function and glutamate system-restricted overexpression of the Nptx2 gene to test the hypothesis that chronic intermittent ethanol-induced Narp, via increased trafficking of AMPAR to the post-synaptic density leads to increased anxiety-like behavior and ethanol self-administration behavior. The studies will involve close collaboration with the Roberto/Siggins, Parsons and Mandyam research components, benefit from the consultation of Dr. Catherine Rivier, and rely closely upon the Animal Models (Koob/George) and Viral Vector (Contet) Cores of the proposed TSRI-ARC.

Public Health Relevance

The proposed studies will reveal neuroadaptive changes in excitatory stress neurocircuitry of the brain that result from chronic intermittent exposure or access to ethanol. Understanding the mechanisms associated with ethanol-induced plasticity of amygdala glutamatergic circuitry may yield new prophylactic and therapeutic approaches to alcoholism.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Comprehensive Center (P60)
Project #
5P60AA006420-31
Application #
8616702
Study Section
Special Emphasis Panel (ZAA1-GG)
Project Start
Project End
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
31
Fiscal Year
2014
Total Cost
$212,375
Indirect Cost
$100,304
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Logrip, Marian L; Oleata, Christopher; Roberto, Marisa (2017) Sex differences in responses of the basolateral-central amygdala circuit to alcohol, corticosterone and their interaction. Neuropharmacology 114:123-134
Natividad, Luis A; Buczynski, Matthew W; Herman, Melissa A et al. (2017) Constitutive Increases in Amygdalar Corticotropin-Releasing Factor and Fatty Acid Amide Hydrolase Drive an Anxious Phenotype. Biol Psychiatry 82:500-510
Kimbrough, Adam; de Guglielmo, Giordano; Kononoff, Jenni et al. (2017) CRF1 Receptor-Dependent Increases in Irritability-Like Behavior During Abstinence from Chronic Intermittent Ethanol Vapor Exposure. Alcohol Clin Exp Res 41:1886-1895
Mason, Barbara J (2017) Emerging pharmacotherapies for alcohol use disorder. Neuropharmacology 122:244-253
Luczak, Susan E; Liang, Tiebing; Wall, Tamara L (2017) Age of Drinking Initiation as a Risk Factor for Alcohol Use Disorder Symptoms is Moderated by ALDH2*2 and Ethnicity. Alcohol Clin Exp Res 41:1738-1744
Irimia, Cristina; Buczynski, Matthew W; Natividad, Luis A et al. (2017) Dysregulated Glycine Signaling Contributes to Increased Impulsivity during Protracted Alcohol Abstinence. J Neurosci 37:1853-1861
Melroy-Greif, Whitney E; Wilhelmsen, Kirk C; Yehuda, Rachel et al. (2017) Genome-Wide Association Study of Post-Traumatic Stress Disorder in Two High-Risk Populations. Twin Res Hum Genet 20:197-207
Varodayan, Florence P; Bajo, Michal; Soni, Neeraj et al. (2017) Chronic alcohol exposure disrupts CB1 regulation of GABAergic transmission in the rat basolateral amygdala. Addict Biol 22:766-778
Roberto, Marisa; Varodayan, Florence P (2017) Synaptic targets: Chronic alcohol actions. Neuropharmacology 122:85-99
Varodayan, Florence P; de Guglielmo, Giordano; Logrip, Marian L et al. (2017) Alcohol Dependence Disrupts Amygdalar L-Type Voltage-Gated Calcium Channel Mechanisms. J Neurosci 37:4593-4603

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