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

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Comprehensive Center (P60)
Project #
3P60AA006420-30S1
Application #
8627352
Study Section
Special Emphasis Panel (ZAA1-GG)
Project Start
Project End
Budget Start
2013-03-01
Budget End
2013-12-31
Support Year
30
Fiscal Year
2013
Total Cost
$1,895
Indirect Cost
$895
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Somkuwar, Sucharita S; Fannon, McKenzie J; Staples, Miranda C et al. (2016) Alcohol dependence-induced regulation of the proliferation and survival of adult brain progenitors is associated with altered BDNF-TrkB signaling. Brain Struct Funct 221:4319-4335
Curran, H Valerie; Freeman, Tom P; Mokrysz, Claire et al. (2016) Keep off the grass? Cannabis, cognition and addiction. Nat Rev Neurosci 17:293-306
Ehlers, Cindy L; Kim, Corinne; Gilder, David A et al. (2016) Lifetime history of traumatic events in a young adult Mexican American sample: Relation to substance dependence, affective disorder, acculturation stress, and PTSD. J Psychiatr Res 83:79-85
Melroy-Greif, Whitney E; Wilhelmsen, Kirk C; Ehlers, Cindy L (2016) Genetic variation in FAAH is associated with cannabis use disorders in a young adult sample of Mexican Americans. Drug Alcohol Depend 166:249-53
Sobieraj, Jeffery C; Kim, Airee; Fannon, McKenzie J et al. (2016) Chronic wheel running-induced reduction of extinction and reinstatement of methamphetamine seeking in methamphetamine dependent rats is associated with reduced number of periaqueductal gray dopamine neurons. Brain Struct Funct 221:261-76
de Guglielmo, Giordano; Crawford, Elena; Kim, Sarah et al. (2016) Recruitment of a Neuronal Ensemble in the Central Nucleus of the Amygdala Is Required for Alcohol Dependence. J Neurosci 36:9446-53
Buczynski, Matthew W; Herman, Melissa A; Hsu, Ku-Lung et al. (2016) Diacylglycerol lipase disinhibits VTA dopamine neurons during chronic nicotine exposure. Proc Natl Acad Sci U S A 113:1086-91
Criado, José R; Gilder, David A; Kalafut, Mary A et al. (2016) Cardiovascular disease risks in adult Native and Mexican Americans with a history of alcohol use disorders: association with cardiovascular autonomic control. Clin Auton Res 26:87-95
Varodayan, Florence P; Soni, Neeraj; Bajo, Michal et al. (2016) Chronic ethanol exposure decreases CB1 receptor function at GABAergic synapses in the rat central amygdala. Addict Biol 21:788-801
Herman, Melissa Ann; Roberto, Marisa (2016) Cell-type-specific tonic GABA signaling in the rat central amygdala is selectively altered by acute and chronic ethanol. Addict Biol 21:72-86

Showing the most recent 10 out of 158 publications