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Effects of cocaine taking and seeking on histone deacetylase class IIa enzyme activity in the nucleus accumbens of rats

Award Number: R01DA042057
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary / Abstract Cocaine addiction is a debilitating mental health disorder that interferes with an individual’s well-being, disrupts relationships, and burdens society. Cocaine, like other drugs of abuse, hijacks the brain’s reward center, producing enduring changes in brain regions, such as the nucleus accumbens (NAc), that perpetuate the cycle of addiction. Preclinical studies show that cocaine and other psychostimulants act as general enhancers of gene expression and that histone deacetylases (HDACs) in the NAc play a key role in the development of cocaine addiction. However, neurobiological understanding of the role of specific HDACs in these processes is limited and there are few in vivo studies on these targets. In response to the need for such studies, this proposal integrates state-of-the-art small animal positron emission tomography (PET) techniques with a model of cocaine self-administration (coc-SA) to study the role of NAc HDAC Class IIa (HDAC5) enzymatic activity during cocaine taking and seeking behaviors. The combination of in vivo neuroimaging and behavioral neuroscience methods in a longitudinal (repeated-measures) design presents an opportunity to advance understanding of the role of epigenetic activity in the NAc during the 4 phases of coc-SA, including acquisition, maintenance, extinction, and reinstatement. Our overall hypothesis is that cocaine will decrease the enzymatic activity of HDAC Class IIa proteins in the NAc, which will statistically explain increases in cocaine taking and seeking behaviors. Three aims will test this hypothesis. (1) Determine HDAC Class IIa enzymatic activity in the NAc using PET imaging and a novel substrate-based PET ligand at baseline and during the phases of coc-SA. (2) Determine the changes in HDAC Class IIa enzymes and protein targets in the NAc at the different phases of coc-SA using immunohistochemistry. (3) Determine the effect of nuclear HDAC5 in the NAc on class IIa HDAC enzymatic activity during cocaine seeking behavior. The combination of non-invasive PET assays with behavioral neuroscience methods to study the role of HDAC Class IIa enzyme activity in the NAc during cocaine taking and seeking behaviors provides a unique strategy to study the neurobiological mechanisms that underlie the stages of addiction. The proposed studies of this application will deliver translational knowledge that addresses theoretical and neurobiological gaps in our understanding of the role of epigenetics in cocaine addiction. This knowledge will aid in the development of novel neurotherapeutics that target epigenetic regulators and treat this devastating mental health disorder.


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: 2023 ( Subtotal = $0 )
2023	2021	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Drug Abuse and Addiction Research Programs	000	5	8/10/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $590,447 )
2021	2021	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Drug Abuse and Addiction Research Programs	000	5	7/9/2021	NON-COMPETING CONTINUATION	$590,447
														Subtotal = $590,447

Issue Date FY: 2020 ( Subtotal = $590,447 )
2020	2020	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Drug Abuse and Addiction Research Programs	000	4	7/9/2020	NON-COMPETING CONTINUATION	$590,447
														Subtotal = $590,447

Issue Date FY: 2019 ( Subtotal = $599,335 )
2019	2019	WAYNE STATE UNIVERSITY	5057 WOODWARD 13 FLOOR	DETROIT	MI	48202	WAYNE	USA	Drug Abuse and Addiction Research Programs	002	3	7/15/2019	NON-COMPETING CONTINUATION	$590,447
2019	2019	WAYNE STATE UNIVERSITY	5057 WOODWARD 13 FLOOR	DETROIT	MI	48202	WAYNE	USA	Drug Abuse and Addiction Research Programs	001	2	5/31/2019	SUPPLEMENT FOR EXPANSION	$421
2019	2019	WAYNE STATE UNIVERSITY	5057 WOODWARD 13 FLOOR	DETROIT	MI	48202	WAYNE	USA	Drug Abuse and Addiction Research Programs	000	2	5/10/2019	SUPPLEMENT FOR EXPANSION	$8,467
														Subtotal = $599,335

Issue Date FY: 2018 ( Subtotal = $598,914 )
2018	2018	WAYNE STATE UNIVERSITY	5057 WOODWARD 13 FLOOR	DETROIT	MI	48202	WAYNE	USA	Drug Abuse and Addiction Research Programs	001	2	7/17/2018	NON-COMPETING CONTINUATION	$590,447
2018	2018	WAYNE STATE UNIVERSITY	5057 WOODWARD 13 FLOOR	DETROIT	MI	48202	WAYNE	USA	Drug Abuse and Addiction Research Programs	000	1	5/7/2018	SUPPLEMENT FOR EXPANSION	$8,467
														Subtotal = $598,914

Issue Date FY: 2017 ( Subtotal = $590,447 )
2017	2017	WAYNE STATE UNIVERSITY	5057 WOODWARD 13 FLOOR	DETROIT	MI	48202	WAYNE	USA	Drug Abuse and Addiction Research Programs	000	1	9/1/2017	NEW	$590,447
														Subtotal = $590,447

Grand Total All Awards = $2,969,590

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Effects of cocaine taking and seeking on histone deacetylase class IIa enzyme activity in the nucleus accumbens of rats

Award Number: R01DA042057

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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