Excessive drinking cost the United States $249 billion in 2010 with 77% attributed to lost productivity, health care costs, and accidents as a result of binge drinking. Despite this high cost, the precise neural mechanisms that underlie escalated drinking remain elusive. The intermittent access (IA) paradigm is a rodent schedule of alcohol drinking that reliably leads to voluntary escalated alcohol intake and preference as well as dysregulated emotional behavior. While numerous neurochemical systems have been identified as playing a role in alcohol- related behavioral pathology, one of the most promising leads for treatment is the Kappa Opioid Receptor (KOR) and its endogenous ligand Dynorphin (Dyn). Consistent with the important role of this system in excessive alcohol drinking, we found that pharmacological blockade of KOR leads to a suppression of escalated IA drinking. Following IA, we found that dynorphin expressing neurons in the Insular Cortex show evidence of increased recruitment. Further, we found that Dyn containing neurons in the Insular Cortex (ICDyn) project to the Substantia Nigra (SN). Taken together, these preliminary data suggest that KOR signaling in the the IC to SN pathway plays a key role in alcohol abuse, potentially via regulation of dysphoric behavioral states. In this proposal we will use a strong multidisciplinary approach to test central hypothesis: Intermittent access to alcohol causes dysregulation of Dyn / KOR systems in the insular cortex to substantia nigra circuit that drive increased ethanol consumption.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Comprehensive Center (P60)
Project #
2P60AA011605-21
Application #
9393522
Study Section
Special Emphasis Panel (ZAA1)
Project Start
Project End
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
21
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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