Endogenous cannabinoid (eCB) signaling in the brain plays a homeostatic role in the constraint and termination of stress responses. During the previous cycle of the TSRI-ARC we found that chronic intermittent EtOH exposure down-regulates eCB signaling in the central nucleus of the amygdala, a brain region critically involved in stress responses and emotional processing. We also found that dependenceassociated anxiety-like behavior and excessive EtOH consumption are alleviated by enhancement of eCB tone. Endocannabinoids are also present in other stress-responsive brain regions such as the basolateral amygdala (BLA) and bed nucleus of the stria terminalis (BNST) where they play a prominent role in the plasticity of excitatory and inhibitory signaling. Dysregulated synaptic function in these regions is believed to contribute to dependence-associated affective disorders and we have gathered preliminary evidence that eCB clearance mechanisms are disrupted in these regions by alcohol dependence. Based on these observations we hypothesize that dysregulated eCB signaling in the BLA and BNST contributes to affective dysregulation and excessive EtOH consumption associated with long-term EtOH exposure. This hypothesis will be tested through three Specific Aims.
Aim 1 will employ biochemical and neurochemical approaches to characterize the nature and persistence of dysregulated eCB function resulting from excessive EtOH exposure.
Aim 2 will characterize the influence of disrupted eCB function in the BLA and BNST on dependence-associated anxiety-like behavior over a period of protracted abstinence. The relative influence of two primary eCB molecules, 2-AG and anandamide (AEA) will be characterized using pharmacological and genetic manipulations of their respective clearance mechanisms.
Aim 3 will characterize the efficacy of selective eCB clearance inhibitors for reducing high levels of EtOH consumption associated with dependence and protracted withdrawal. The experimental design incorporates two distinct animal models of excessive drinking to index the development of eCB disruptions along the trajectory from chronic binge drinking to excessive EtOH consumption motivated by dependence.

Public Health Relevance

Withdrawal-related emotional distress is relieved by renewed alcohol consumption and this propels excessive drinking by alcoholics. This project will characterize the role of dysregulated endocannabinoid signaling in this process. Results from these experiments are likely to highlight previously unrecognized mechanisms in the etiology of alcohol dependence and may identify novel therapeutic targets for alcoholism

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Comprehensive Center (P60)
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Scripps Research Institute
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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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