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New Therapeutics for Treating Cocaine Addiction Targeting D1-D2 Heteromers

Award Number: U18DA052509
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: KDA (KNOWLEDGE/DEVELOPMENT/APPLICATION)
PERIOD OF PERFORMANCE START DATE: 06/02/2021
PERIOD OF PERFORMANCE END DATE: 09/29/2023

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New Therapeutics for Treating Cocaine Addiction Targeting D1-D2 Heteromers - PROJECT SUMMARY/ABSTRACT Cocaine abuse has reached epidemic levels in North America. By 2018, over 5.5 million Americans over the age of 12 had used cocaine within the past year, and almost 1 million meet DSM-IV criteria for addiction. Overdose related deaths have more than doubled from 2007 to 2019, reaching almost 16,000 deaths in 2019. Currently, there are no FDA approved medications available for treating cocaine use disorders. About 24% of those seeking treatment will relapse within a year following treatment. Relapse rates in abstinent patients are high, because the currently available treatment regimens do not adequately address addiction. Chronic cocaine abuse leads to lasting adaptations in the limbic, motivational, and executive areas of the brain. Glutamate homeostasis is altered, and results in changes in receptor expression in the ventral tegmental area (VTA) and changes in signaling into the VTA and prefrontal cortex (PFC); relapse is associated with enhanced glutamate transmission from the PFC and amygdala into the VTA. These lasting changes result from upregulation of short-lived CREB and sustained elevation and accumulation of FosB, especially in the nucleus accumbens. By reducing the expression of FosB in the nucleus accumbens, the lasting neurological changes associated with the addictive state can be mitigated, and cocaine addiction can be successfully treated. To date, the search for a medication that can effect this change has not been successful. One potential unexplored avenue involves targeting D1-D2 heterodimers, which are largely expressed selectively in the medium spiny neurons in the nucleus accumbens shell. Mounting evidence indicates that selectively agonizing the D1-D2 heterodimers can block upregulation of CREB and the resulting overexpression of FosB in the nucleus accumbens. Thus, this approach represents a novel route for treating cocaine abuse and relapse, and holds high potential for treating patients with CUD and keeping cocaine free patients abstinent. In order to fulfill this goal, we will first focus on the synthesis of novel heterobivalent molecules which target the D1-D2 heterodimer. Second, we will evaluate the ligands for affinity, selectivity, and agonist activity at the D1-D2 heteromer complex. The goal of this project is to develop a selective D1-D2 heterodimer agonist as a novel potential therapy for cocaine use disorders.


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 = $0 )
2024	2020	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Drug Use and Addiction Research Programs	000	2	3/4/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Drug Use and Addiction Research Programs	002	2	11/16/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2022	2020	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Drug Use and Addiction Research Programs	001	2	10/20/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$9,046
2022	2020	MCLEAN HOSPITAL CORPORATION, THE	115 MILL ST	BELMONT	MA	02478	MIDDLESEX	USA	Drug Use and Addiction Research Programs	000	1	10/20/2021	NEW	-$9,046
2022	2020	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Drug Use and Addiction Research Programs	003	2	8/23/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = -$12,565 )
2021	2020	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Drug Use and Addiction Research Programs	001	2	6/14/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$96,867
2021	2020	MCLEAN HOSPITAL CORPORATION, THE	115 MILL ST	BELMONT	MA	02478	MIDDLESEX	USA	Drug Use and Addiction Research Programs	000	1	6/14/2021	NEW	-$109,432
														Subtotal = -$12,565

Issue Date FY: 2020 ( Subtotal = $229,199 )
2020	2020	MCLEAN HOSPITAL CORPORATION, THE	115 MILL ST	BELMONT	MA	02478	MIDDLESEX	USA	Drug Use and Addiction Research Programs	000	1	9/22/2020	NEW	$229,199
														Subtotal = $229,199

Grand Total All Awards = $216,634

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New Therapeutics for Treating Cocaine Addiction Targeting D1-D2 Heteromers

Award Number: U18DA052509

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: KDA (KNOWLEDGE/DEVELOPMENT/APPLICATION)

PERIOD OF PERFORMANCE START DATE: 06/02/2021

PERIOD OF PERFORMANCE END DATE: 09/29/2023

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