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Amphetamine During Adolescence Reroutes Mesolimbic Dopamine Axons to the Prefrontal Cortex via DCC Signaling

Award Number: F31DA041188
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/15/2016
PERIOD OF PERFORMANCE END DATE: 09/14/2019

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Amphetamine During Adolescence Reroutes Mesolimbic Dopamine Axons to the Prefrontal Cortex via DCC Signaling - Adolescence is the period in which individuals are most likely to initiate the consumption of drugs of abuse. The onset of drug use during adolescence, however, also confers the highest risk of progressing from recreational use to addiction. This suggests that drug exposure during the critical window of adolescence may interfere with ongoing neuronal development and cause behavioral changes which facilitate subsequent substance abuse and addiction. However, there is still a significant lack of knowledge about the mechanisms accounting for these age-dependent effects of drug exposure. To address this gap in our knowledge, it is important to understand (1) the mechanism underlying the interaction between drugs of abuse and the adolescent brain, (2) how these interactions disrupt the development of neuronal circuitry, and (3) the resulting long-lasting changes in addiction-relevant behaviors. The netrin-1 guidance cue receptor DCC has recently emerged as a key molecular player in the adolescent organization of the mesocorticolimbic dopamine system, and expression of DCC is regulated by adolescent exposure to drugs of abuse. Exposure to the stimulant drug of abuse, amphetamine, during early adolescence disrupts the development of dopamine input to the medial prefrontal cortex of mice via alterations to DCC signaling. The long-term goal of the studies proposed here is to determine if amphetamine in adolescence induces the ectopic growth of mesolimbic dopamine axons to the medial prefrontal cortex by disrupting DCC-mediated guidance events, and to identify the enduring consequences on prefrontal cortex-dependent cognitive behavior. These neurobiological and behavioral alterations may underlie heightened vulnerability to progress to addiction in individuals that initiate drug use in adolescence. The experiments will employ neuroanatomical, gene transfection, and behavioral techniques in a mouse model to assess two specific aims. Aim 1 will determine whether amphetamine in adolescence increases prefrontal cortex dopamine innervation by promoting the ectopic growth of mesolimbic dopamine axons to this region. Aim 2 will assess the role of DCC-mediated netrin-1 signaling in the neuroanatomical and behavioral effects of amphetamine in adolescence. The results of the proposed research will move the field toward a clearer understanding of the mechanisms accounting for the age-dependent effects of drug exposure on addiction vulnerability. These results could be used to facilitate development of individualized prevention and treatment strategies aimed at adolescent drug users, who are at heightened risk to progress to addiction. !


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 = -$2,100 )
2024	2018	THE ROYAL INSTITUTION FOR THE ADVANCEMENT OF LEARNING	845 ST SHERBROOKE W	MONTREAL	QC			CAN	Drug Use and Addiction Research Programs	000	3	10/1/2023	NON-COMPETING CONTINUATION	-$2,100
														Subtotal = -$2,100

Issue Date FY: 2022 ( Subtotal = $2,100 )
2022	2018	ROYAL INSTITUTION FOR THE ADVANCEMENT OF LEARNING / MCGILL	845 RUE SHERBROOKE O	MONTREAL	PQ			CAN	Drug Use and Addiction Research Programs	000	3	9/23/2022	NON-COMPETING CONTINUATION	$2,100
														Subtotal = $2,100

Issue Date FY: 2021 ( Subtotal = -$3,937 )
2021	2018	REDACTED DUE TO PII		MONTREAL	PQ			CAN	Drug Use and Addiction Research Programs	000	3	1/12/2021	NON-COMPETING CONTINUATION	-$3,937
														Subtotal = -$3,937

Issue Date FY: 2019 ( Subtotal = -$15,275 )
2019	2018	ROYAL INSTITUTE FOR ADVANCEMENT OF LEARNING MCGILL	845 SHERBROOKE STREET WEST	MONTREAL	PQ	H3A 0G4		CAN	Drug Use and Addiction Research Programs	001	3	3/12/2019	NON-COMPETING CONTINUATION	-$2,100
2019	2018	REDACTED DUE TO PII		MONTREAL	PQ	H3A 0G4		CAN	Drug Use and Addiction Research Programs	000	3	3/11/2019	NON-COMPETING CONTINUATION	-$13,175
														Subtotal = -$15,275

Issue Date FY: 2018 ( Subtotal = $4,200 )
2018	2018	ROYAL INSTITUTE FOR ADVANCEMENT OF LEARNING MCGILL	845 SHERBROOKE STREET WEST	MONTREAL	PQ	H3A 0G4		CAN	Drug Use and Addiction Research Programs	001	3	8/29/2018	NON-COMPETING CONTINUATION	$4,200
														Subtotal = $4,200

Issue Date FY: 2017 ( Subtotal = $4,200 )
2017	2017	ROYAL INSTITUTION FOR THE ADVANCEMENT OF LEARNING / MCGILL UNIVERSITY	845 RUE SHERBROOKE O BUREAU 318	MONTREAL	PQ	H3A 0G4		CAN	Drug Use and Addiction Research Programs	001	2	8/18/2017	NON-COMPETING CONTINUATION	$4,200
														Subtotal = $4,200

Issue Date FY: 2016 ( Subtotal = $4,200 )
2016	2016	MCGILL UNIVERSITY	361 UNIVERSITY STREET	MONTREAL, QUEBEC				CAN	Drug Use and Addiction Research Programs	001	1	9/2/2016	NEW	$4,200
														Subtotal = $4,200

Grand Total All Awards = -$6,612

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Amphetamine During Adolescence Reroutes Mesolimbic Dopamine Axons to the Prefrontal Cortex via DCC Signaling

Award Number: F31DA041188

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/15/2016

PERIOD OF PERFORMANCE END DATE: 09/14/2019

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