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Brain exosomes mediate cocaine-induced addiction

Award Number: R01DA044489
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2017
PERIOD OF PERFORMANCE END DATE: 05/31/2024

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Brain exosomes mediate cocaine-induced addiction - ABSTRACT While the development of addictive behaviors and the associated short- and long-term neuroadaptations after exposure to cocaine have been extensively studied, the mechanisms of cocaine addiction have not been fully elucidated. Using a novel method developed in our laboratory, we have isolated exosomes from the mouse brain and found in preliminary studies that chronic cocaine treatment increased levels of exosomes in the brain and changed the protein and lipid content of exosomes. Since cocaine has been shown to cause dysfunctions in the endosomal/autophagic/lysosomal system, we hypothesize that cocaine enhances exosome secretion in order to release accumulation of cellular materials caused by the disturbed degradation pathway. However, recent studies indicate that exosomes also serve as intercellular communication vehicles. Therefore, we suggest that exosome secretion is involved in the addiction process by transferring addiction-related proteins, lipids, and RNAs to target cells. We propose to test this hypothesis by characterizing the exosomes isolated from the brain of mice treated with cocaine or saline as control. Time course of changes in the level and cargo compositions of exosomes during non-contingent and contingent cocaine administration, followed by withdrawal (Aim 1), brain regional comparison of exosomal characteristics (Aim 2), and the direct effects of isolated exosomes on cocaine-related cellular and behavioral changes (Aim 3) would identify exosome- dependent and brain region specific mechanisms that underlie addictive behaviors. We have identified four exosomal populations, and in Aim 1 we propose to characterize the exosome populations affected by acute and chronic cocaine treatment. We will determine secretion levels of exosomes and analyze their cocaine- dependent proteomics, lipidomics, and RNA profiles. While global analyses of these molecules are our goal, a special focus will be given to BDNF, NMDA ε2, and gangliosides based on our preliminary results that have shown cocaine-induced changes in the levels of these molecules in exosomes. In Aim 2 we will identify brain regions and cellular changes involved in cocaine-induced secretion of exosomes containing cocaine-altered proteins, lipids, and RNAs in order to determine the role of exosomes in the induction, sensitization, or withdrawal phases of addiction. In Aim 3 we will evaluate roles of exosomes in cocaine addiction. The effects of exosomes derived from cocaine-treated mice, as well as, from in vitro cocaine-treated primary cultured cortical neurons and glial cells, on addiction-related molecular, cellular, and behavioral changes will be tested in naïve mice. Future studies will examine whether some of the cocaine-induced changes in proteins, lipids, and RNAs, found in brain exosomes are also observed in cerebrospinal fluid and serum exosomes isolated from cocaine-addicted humans. The studies proposed here aim to give an insight into mechanisms behind the role of exosomes in cocaine addiction and may lead to finding new targets for addiction therapy and/or new biomarkers for cocaine addiction and withdrawal.


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 = -$64 )
2025	2021	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	140 OLD ORANGEBURG RD BLDG 35	ORANGEBURG	NY	10962	ROCKLAND	USA	Drug Use and Addiction Research Programs	000	5	10/15/2024	NON-COMPETING CONTINUATION	-$64
														Subtotal = -$64

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	RESEARCH FOUNDATION FOR MENTAL HYGIENE INC	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Drug Use and Addiction Research Programs	000	5	5/11/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $423,068 )
2021	2021	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Drug Use and Addiction Research Programs	000	5	5/19/2021	NON-COMPETING CONTINUATION	$423,068
														Subtotal = $423,068

Issue Date FY: 2020 ( Subtotal = $431,937 )
2020	2020	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Drug Use and Addiction Research Programs	000	4	5/6/2020	NON-COMPETING CONTINUATION	$431,937
														Subtotal = $431,937

Issue Date FY: 2019 ( Subtotal = $440,548 )
2019	2019	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Drug Use and Addiction Research Programs	000	3	5/15/2019	NON-COMPETING CONTINUATION	$440,548
														Subtotal = $440,548

Issue Date FY: 2018 ( Subtotal = $450,004 )
2018	2018	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Drug Use and Addiction Research Programs	000	2	5/8/2018	NON-COMPETING CONTINUATION	$450,004
														Subtotal = $450,004

Issue Date FY: 2017 ( Subtotal = $465,174 )
2017	2017	RESEARCH FOUNDATION FOR MENTAL HYGIENE INC	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Drug Use and Addiction Research Programs	000	1	8/29/2017	NEW	$465,174
														Subtotal = $465,174

Grand Total All Awards = $2,210,667

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Brain exosomes mediate cocaine-induced addiction

Award Number: R01DA044489

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2017

PERIOD OF PERFORMANCE END DATE: 05/31/2024

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