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Characterization of alcohol interoceptive effects following predator odor exposure: relevance to PTSD

Award Number: R01AA026537
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: 09/12/2017
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Characterization of alcohol interoceptive effects following predator odor exposure: relevance to PTSD - Project Summary Individuals who suffer from post-traumatic stress disorder (PTSD) are often at higher risk for developing comorbid alcohol use disorder (AUD). Studying individual differences in response to stress is important as not everyone who experiences trauma or witnesses a traumatic event develops PTSD. In preclinical models, exposure to the scent of a predator is commonly used for the study of PTSD-like phenotypes. During the current funding period and in this renewal we use exposure to 2,5-dihydro-2,4,5-trimethylthiazoline (TMT) a synthetically derived component of fox feces as the predator odor stressor. We find individual differences in stress reactivity specifically in the engagement of digging in the bedding and immobility behavior during the TMT exposure. While most rats engage primarily in immobility behavior (TMT-1 subgroup), we find a subset of rats engage in a high degree of digging behavior and less immobility (TMT-2 subgroup). This TMT-2 subgroup also shows heightened corticosterone in response to TMT, persistent escalation in alcohol self-administration, and increased TMT- contextual conditioning whereas rats in the TMT-1 subgroup do not. Moreover, while several factors contribute to alcohol drinking, the interoceptive effects associated with drinking are important to study as these are a key part of the drinking experience and can drive ongoing drinking. Further, dysregulation of interoceptive processing is a common feature in several mental health disorders, including PTSD. As such, it is important to consider that escalations in alcohol drinking that emerge following a stressor exposure, may be related to changes in sensitivity to the interoceptive effects of alcohol. Therefore, it is highly significant that we find potentiated sensitivity to the interoceptive effects of alcohol (as measured in a Pavlovian drug discrimination procedure) 2 weeks after TMT exposure, driven by the TMT-2 subgroup. We also find changes in GABAA and NMDA receptor gene expression, primary components of alcohol interoceptive effects, in the anterior insular cortex (aIC) and the nucleus accumbens core (AcbC), key circuitry that we have identified as underlying alcohol interoceptive effects. Lastly, there is a growing body of PTSD literature implicating dysregulated glutamatergic systems in PTSD pathology. We find that treatment with a metabotropic glutamate receptor subtype 3 (mGlu3) negative allosteric modulator (NAM) prior to TMT exposure attenuates some of the adaptations in GABAA and NMDA receptors. Overall, we hypothesize that 1) decreased activity of aICAcbC projections influenced by changes in GABAA and NMDA receptor expression, drive potentiated sensitivity to alcohol 2 weeks after TMT exposure, and 2) that mGlu3 signaling during TMT exposure contributes to these lasting changes. These innovative studies will allow for a broader understanding of the consequences of stressor exposure on alcohol interoceptive effects, as this can lead to a better understanding of interoceptive processing in PTSD, which may influence alcohol drinking.


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: 2025 ( Subtotal = $423,258 )
2025	2025	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Alcohol Research Programs	002	8	5/1/2025	NON-COMPETING CONTINUATION	$423,258
2025	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Alcohol Research Programs	001	6	2/12/2025	COMPETING CONTINUATION	$66
2025	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Alcohol Research Programs	000	5	2/12/2025	NON-COMPETING CONTINUATION	-$66
														Subtotal = $423,258

Issue Date FY: 2024 ( Subtotal = $427,456 )
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Alcohol Research Programs	000	7	2/15/2024	NON-COMPETING CONTINUATION	$384,711
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Alcohol Research Programs	001	7	5/10/2024	NON-COMPETING CONTINUATION	$42,745
														Subtotal = $427,456

Issue Date FY: 2023 ( Subtotal = $380,451 )
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Alcohol Research Programs	001	6	4/20/2023	COMPETING CONTINUATION	$380,451
2023	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Alcohol Research Programs	000	5	4/19/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $380,451

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2018	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Alcohol Research Programs	000	2	8/12/2022	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $384,119 )
2021	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Alcohol Research Programs	000	5	7/2/2021	NON-COMPETING CONTINUATION	$384,119
														Subtotal = $384,119

Issue Date FY: 2020 ( Subtotal = $482,246 )
2020	2020	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Alcohol Research Programs	000	4	6/10/2020	NON-COMPETING CONTINUATION	$482,246
														Subtotal = $482,246

Issue Date FY: 2019 ( Subtotal = $482,246 )
2019	2019	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Alcohol Research Programs	000	3	7/11/2019	NON-COMPETING CONTINUATION	$482,246
														Subtotal = $482,246

Issue Date FY: 2018 ( Subtotal = $482,246 )
2018	2018	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Alcohol Research Programs	000	2	6/5/2018	NON-COMPETING CONTINUATION	$384,119
2018	2018	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Alcohol Research Programs	001	2	9/12/2018	SUPPLEMENT FOR EXPANSION	$98,127
														Subtotal = $482,246

Issue Date FY: 2017 ( Subtotal = $371,952 )
2017	2017	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Alcohol Research Programs	000	1	9/11/2017	NEW	$371,952
														Subtotal = $371,952

Grand Total All Awards = $3,433,974

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Characterization of alcohol interoceptive effects following predator odor exposure: relevance to PTSD

Award Number: R01AA026537

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: 09/12/2017

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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