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Gene-environment interaction: the brain CRF system in alcohol preferring msP rats

Award Number: R37AA017447
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: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Gene-environment interaction: the brain CRF system in alcohol preferring msP rats - Program Director/Principal Investigator (Last, First, Middle): Alcoholism is a chronically relapsing disorder that develops over time and is characterized by the transition from recreational alcohol use to abuse and dependence. Negative emotional states, such as posttraumatic stress disorder (PTSD) or anxiety, influenced by genetic factors or determined by environmental conditions contribute to shaping this transition. On the other hand, chronic exposure to alcohol is a major determinant for the occurrence of mood disorders (e.g., anxiety, depression, PTSD) and negative emotional states (i.e., dysphoria, irritability). The amygdalar nuclei [both the central nucleus of the amygdala (CeA) and basolateral amygdala (BLA)] are considered a hub for negative emotional circuitry, and the role of the stress peptide corticotropin-releasing factor (CRF) in this brain structure is critical for both development of alcohol dependence and mood disorders/negative affect. During the previous funding period we provided essential new insight into the relationship between innate overexpression of the CRF1 receptor system, stress hypersensitivity and excessive ethanol consumption in genetically selected Marchigian Sardinian (msP) rats. Our most recent results show that enhanced CRF signaling in msP rats is responsible for increased hydrolytic activity of fatty acid amide hydrolase (FAAH) and blunted endocannabinoid (eCB) signaling in the CeA/BLA, leading to enhanced GABA and glutamate transmission in the amygdala. Our hypothesis is that such alterations contribute to enhance stress sensitivity and to exacerbate anxiety-like symptoms in the msP rats, which may increase drinking to alleviate these negative conditions. Understanding the mechanisms through with innate and environmental factors act/interact to dysregulate CRF/eCB transmission in the BLA and CeA will provide new insight into the etiopathology of alcoholism, aiding the development of new therapeutics for this still largely untreated medical condition. The research plan for this competitive renewal is to investigate how alteration of eCB signaling in the amygdala triggered by innate (in msP rats) or EtOH-induced (post-dependent Wistars) upregulation of the CRF1 system contributes to excessive alcohol drinking and exacerbates maladaptive conditioned fear responses, similar to symptoms of PTSD in humans. The ability to restore normal eCB function by FAAH inhibition, and therefore to counteract excessive drinking and normalize fear responses, will be also studied. A better understanding of the molecular mechanism underlying genotypic differences of the msP compared to outbred Wistar rats and of neuroadaptations following exposure to alcohol, will provide novel insight into the innate susceptibility to develop Alcohol Use Disorder and will be useful toward the development of new therapeutic agents to alleviate alcohol dependence. RELEVANCE (See instructions): The Marchigian Sardinian alcohol-preferring (msP) rats represent an unique rat model in which genetic selection for high alcohol preference has led to co-segregation of elevated sensitivity to stress and anxiety. The goal of this project is to provide a systematic investigation at the molecular, neurochemical and behavioral levels of the impact of these heritable factors and biological mechanisms in the etiology of anxiety and alcohol drinking behavior. These studies may help identify biological targets for the development of pharmacological treatment for alcoholism and the frequent co- occurrence anxiety related disorders, such as post-traumatic stress disorder (PTSD).


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: 2024 ( Subtotal = $355,896 )
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	14	6/19/2024	NON-COMPETING CONTINUATION	$355,896
														Subtotal = $355,896

Issue Date FY: 2023 ( Subtotal = $351,414 )
2023	2023	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	13	6/21/2023	NON-COMPETING CONTINUATION	$351,414
														Subtotal = $351,414

Issue Date FY: 2022 ( Subtotal = $346,185 )
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	12	8/26/2022	NON-COMPETING CONTINUATION	$346,185
														Subtotal = $346,185

Issue Date FY: 2021 ( Subtotal = $365,560 )
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	002	11	9/10/2021	EXTENSION WITH OR WITHOUT FUNDS	$181,831
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	11	6/30/2021	EXTENSION WITH OR WITHOUT FUNDS	$365,560
2021	2020	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	001	10	9/10/2021	NON-COMPETING CONTINUATION	-$181,831
														Subtotal = $365,560

Issue Date FY: 2020 ( Subtotal = $377,663 )
2020	2020	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	10	6/23/2020	NON-COMPETING CONTINUATION	$377,663
														Subtotal = $377,663

Issue Date FY: 2019 ( Subtotal = $377,663 )
2019	2019	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	9	6/18/2019	NON-COMPETING CONTINUATION	$377,663
														Subtotal = $377,663

Issue Date FY: 2018 ( Subtotal = $377,663 )
2018	2018	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	8	6/25/2018	NON-COMPETING CONTINUATION	$377,663
														Subtotal = $377,663

Issue Date FY: 2017 ( Subtotal = $386,123 )
2017	2017	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	001	7	7/3/2017	NON-COMPETING CONTINUATION	$377,663
2017	2016	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	6	12/5/2016	COMPETING CONTINUATION	$8,460
														Subtotal = $386,123

Issue Date FY: 2016 ( Subtotal = $396,900 )
2016	2016	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	001	6	9/19/2016	COMPETING CONTINUATION	$0
2016	2016	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Alcohol Research Programs	000	6	8/23/2016	COMPETING CONTINUATION	$396,900
														Subtotal = $396,900

Grand Total All Awards = $3,335,067

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Gene-environment interaction: the brain CRF system in alcohol preferring msP rats

Award Number: R37AA017447

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: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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