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Synaptic Correlates of Vulnerability and Resilience to Alcohol Use Disorder

Award Number: R01AA017531
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2009
PERIOD OF PERFORMANCE END DATE: 01/31/2031

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Synaptic Correlates of Vulnerability and Resilience to Alcohol Use Disorder - PROJECT SUMMARY Binge drinking, defined as consumption of enough alcohol to attain blood levels of at least 80 mg% in a single session, is a well-established risk factor for alcohol use disorder (AUD) and the prevalence of these risky drinking patterns has been rising sharply in several demographic groups, including adults and women. Importantly, many binge drinkers reach blood levels 2-3X higher than 80 mg% during these heavy drinking episodes and while excellent preclinical models of binge drinking have been established, most do not result in the high blood alcohol levels often seen in binge drinkers. The overarching goal of this project is to leverage a rodent chronic intermittent ethanol vapor regimen (cBE) adapted to model heavy binge drinking patterns to identify neural circuitry that may play a causal role in key AUD-related behaviors that emerge following cBE withdrawal. One of the most consistent findings from human functional imaging studies is that individuals with AUD show stronger subjective responding and cortical/subcortical reactivity to alcohol and alcohol cues but blunted responsivity to non-alcohol rewards, relative to healthy controls. This overvaluing of alcohol, termed salience misattribution, correlates with craving, is a core element of many diagnostic criteria of AUD, and is diminished with successful AUD treatment. Despite the clinical importance of salience misattribution, animal models of this clinically important phenotype are lacking. By integrating cBE and a daily home-cage 3 bottle choice drinking regimen (14% ethanol, 0.5% sucrose, water), our preliminary data demonstrate that repeated cycles of cBE significantly increases ethanol drinking and ethanol cue reactivity while simultaneously decreasing these measures for sucrose in male and female rats. The first aim will further validate the cBE model and test the hypothesis that salience misattribution develops, in part, via a shift in the primary motivation to obtain ethanol away from positive reinforcement toward the relief from hyperkatifeia, a negative emotion-like state that emerges during withdrawal. Building on published and preliminary data, the second aim will use operant approaches to test the hypothesis that cBE increases both appetitive (motivational) and consummatory ethanol drinking-related measures while decreasing these measures for sucrose. Chemogenetic approaches will then be used to determine if two key limbic circuits implicated in salience encoding and negative emotion- like behaviors (basloteral amygdala→ventral subiculum; ventral subiculum→nucleus accumbens) play a causal role in cBE-related behavioral phenotypes. A final aim will integrate ex vivo and in vivo approaches to test the hypothesis that cBE increases synaptic excitability within these two limbic circuits. Together these studies seek to establish a novel rodent model to study the effects of binge-like ethanol exposure on an understudied and clinically import AUD-related phenotypes and identify adaptations in limbic circuitry that play a causal role in the expression of these maladaptive behaviors.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $433,840 )
2026	2026	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	16	5/5/2026	COMPETING CONTINUATION	$433,840
														Subtotal = $433,840

Issue Date FY: 2014 ( Subtotal = $0 )
2014	2013	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	5	4/1/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2013 ( Subtotal = $311,069 )
2013	2013	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	5	5/14/2013	NON-COMPETING CONTINUATION	$311,069
2013	2013	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	001	5	4/1/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $311,069

Issue Date FY: 2012 ( Subtotal = $334,483 )
2012	2012	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	4	4/20/2012	NON-COMPETING CONTINUATION	$334,483
														Subtotal = $334,483

Issue Date FY: 2011 ( Subtotal = $334,483 )
2011	2011	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	3	5/20/2011	NON-COMPETING CONTINUATION	$334,483
														Subtotal = $334,483

Issue Date FY: 2010 ( Subtotal = $347,985 )
2010	2010	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	2	5/18/2010	NON-COMPETING CONTINUATION	$347,985
														Subtotal = $347,985

Issue Date FY: 2009 ( Subtotal = $351,500 )
2009	2009	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	1	4/20/2009	NEW	$351,500
														Subtotal = $351,500

Grand Total All Awards = $2,113,360

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Synaptic Correlates of Vulnerability and Resilience to Alcohol Use Disorder

Award Number: R01AA017531

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/01/2009

PERIOD OF PERFORMANCE END DATE: 01/31/2031

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