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Methamphetamine Toxicity and Corticostriatal Glutamate

Award Number: R01DA007606
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/1992
PERIOD OF PERFORMANCE END DATE: 04/30/2017

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Methamphetamine Toxicity and Corticostriatal Glutamate - DESCRIPTION (provided by applicant): The adverse effects of methamphetamine (METH) are of international and national concern (SAMSHA, 2010; UNODC, 2010). It is now clear the METH has toxic effects on the human brain. Animal studies have provided valuable information on the neurotoxic mechanisms and consequences of METH but the precise means by which METH causes brain damage remain unclear It is commonly and logically assumed that its neurotoxic effects are derived from its direct action on the brain. However, largely ignored are the myriad peripheral effects that might contribute to METH neurotoxicity. A likely peripheral source of these effects is the liver. It is known that the liver is a direct target of METH and man other drugs of abuse but no consideration has been given to whether liver or other peripheral organ damage is related to METH neurotoxicity. However, a well known consequence of acute liver damage is the neuropsychiatric syndrome, hepatic encephalopathy (HE). The key mediator of HE is hyperammonemia. Ammonia (NH3) causes neuronal damage through mechanisms strikingly similar to excitotoxicity and oxidative stress that have been implicated in METH-induced neurotoxicity. Specifically, NH3 increases glutamate (GLU) release, activates NMDA receptors, and down- regulates the GLU transporter, while inhibiting glutamine synthetase (condensation of GLU) and increasing superoxide radical and nitric oxide formation. This proposal will examine a new concept related to the neurotoxicity of METH by identifying a peripherally derived, novel mediator of METH-induced neurotoxicity based on exciting preliminary evidence implicating peripheral NH3 in the neurotoxic effects of METH. The long term goal is to identify the determinants of METH neurotoxicity to assess the risk to human health of repeated METH exposures. The objective is to elucidate the mechanisms by which METH causes damage to dopamine (DA) terminals. The central hypothesis is that METH causes a hyperammonemic state that triggers interdependent and convergent alterations in GLU homeostasis, excitotoxicity, and oxidative stress to GLUergic and DAergic regulatory proteins. These changes in turn, promote a feed-forward process that culminates in the classical METH neurotoxicity. Specific Aim 1 will identify NH3 as a mediator of METH-induced damage to DA terminals while Specific Aim 2 will elucidate the excitotoxic/glutamatergic mechanisms underlying the effects of NH3 in METH- induced damage to DA. Specific Aim 3 will build upon the other aims and determine if NH3 contributes to oxidative stress to DA terminals through a dysregulation of GLU transmission. Overall, the findings should have a positive impact because the identification of peripheral NH3 as a small molecule mediator of METH can lead to feasible therapeutic strategies for the treatment of METH overdose and neurotoxicity while fundamentally advancing the field of drug-induced brain damage in general. The proposal highlights the broader significance of peripheral organ toxicity in mediating neurological consequences.


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: 2018 ( Subtotal = $0 )
2018	2016	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Drug Use and Addiction Research Programs	000	26	8/23/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $303,145 )
2016	2016	INDIANA UNIVERSITY, BLOOMINGTON	509 EAST 3RD STREET	BLOOMINGTON	IN	47405	MONROE	USA	Drug Use and Addiction Research Programs	000	26	4/8/2016	NON-COMPETING CONTINUATION	$303,145
														Subtotal = $303,145

Issue Date FY: 2015 ( Subtotal = $296,249 )
2015	2015	UNIVERSITY OF TOLEDO-HEALTH SCIENCE CAMPUS	3000 ARLINGTON AVENUE	TOLEDO	OH	43614	LUCAS	USA	Drug Use and Addiction Research Programs	002	24	9/9/2015	NON-COMPETING CONTINUATION	-$255,000
2015	2015	UNIVERSITY OF TOLEDO-HEALTH SCIENCE CAMPUS	3000 ARLINGTON AVENUE	TOLEDO	OH	43614	LUCAS	USA	Drug Use and Addiction Research Programs	000	24	4/24/2015	NON-COMPETING CONTINUATION	$296,250
2015	2015	INDIANA UNIVERSITY, BLOOMINGTON	509 EAST 3RD STREET	BLOOMINGTON	IN	47405	MONROE	USA	Drug Use and Addiction Research Programs	001	25	9/9/2015	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$254,999
														Subtotal = $296,249

Issue Date FY: 2014 ( Subtotal = $309,608 )
2014	2014	UNIVERSITY OF TOLEDO-HEALTH SCIENCE CAMPUS	3000 ARLINGTON AVENUE	TOLEDO	OH	43614	LUCAS	USA	Drug Use and Addiction Research Programs	000	23	4/4/2014	NON-COMPETING CONTINUATION	$309,608
														Subtotal = $309,608

Issue Date FY: 2013 ( Subtotal = $303,435 )
2013	2013	UNIVERSITY OF TOLEDO-HEALTH SCIENCE CAMPUS	3000 ARLINGTON AVENUE	TOLEDO	OH	43614	LUCAS	USA	Drug Use and Addiction Research Programs	001	22	5/16/2013	NON-COMPETING CONTINUATION	$18,964
2013	2013	UNIVERSITY OF TOLEDO-HEALTH SCIENCE CAMPUS	3000 ARLINGTON AVENUE	TOLEDO	OH	43614	LUCAS	USA	Drug Use and Addiction Research Programs	000	22	4/17/2013	NON-COMPETING CONTINUATION	$284,471
														Subtotal = $303,435

Issue Date FY: 2012 ( Subtotal = $333,281 )
2012	2012	UNIVERSITY OF TOLEDO-HEALTH SCIENCE CAMPUS	3000 ARLINGTON AVENUE	TOLEDO	OH	43614	LUCAS	USA	Drug Use and Addiction Research Programs	001	21	5/31/2012	COMPETING CONTINUATION	$333,281
2012	2011	UNIVERSITY OF TOLEDO-HEALTH SCIENCE CAMPUS	3000 ARLINGTON AVENUE	TOLEDO	OH	43614	LUCAS	USA	Drug Use and Addiction Research Programs	000	20	5/30/2012	NON-COMPETING CONTINUATION	$0
														Subtotal = $333,281

Issue Date FY: 2011 ( Subtotal = $314,019 )
2011	2011	UNIVERSITY OF TOLEDO-HEALTH SCIENCE CAMPUS	3000 ARLINGTON AVENUE	TOLEDO	OH	43614	LUCAS	USA	Drug Use and Addiction Research Programs	000	20	5/9/2011	NON-COMPETING CONTINUATION	$314,019
														Subtotal = $314,019

Issue Date FY: 2010 ( Subtotal = $472,230 )
2010	2010	UNIVERSITY OF TOLEDO-HEALTH SCIENCE CAMPUS	3000 ARLINGTON AVENUE	TOLEDO	OH	43614	LUCAS	USA	Drug Use and Addiction Research Programs	001	19	6/29/2010	NON-COMPETING CONTINUATION	$0
2010	2010	UNIVERSITY OF TOLEDO-HEALTH SCIENCE CAMPUS	3000 ARLINGTON AVENUE	TOLEDO	OH	43614	LUCAS	USA	Drug Use and Addiction Research Programs	000	19	4/30/2010	NON-COMPETING CONTINUATION	$472,230
														Subtotal = $472,230

Issue Date FY: 2009 ( Subtotal = $477,002 )
2009	2009	UNIVERSITY OF TOLEDO-HEALTH SCIENCE CAMPUS	3000 ARLINGTON AVENUE	TOLEDO	OH	43614	LUCAS	USA	Drug Use and Addiction Research Programs	003	18	9/28/2009	SUPPLEMENT FOR EXPANSION	$150,000
2009	2009	UNIVERSITY OF TOLEDO-HEALTH SCIENCE CAMPUS	3000 ARLINGTON AVENUE	TOLEDO	OH	43614	LUCAS	USA	Drug Use and Addiction Research Programs	002	18	4/27/2009	NON-COMPETING CONTINUATION	$327,002
2009	2008	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Drug Use and Addiction Research Programs	000	16	12/5/2008	NON-COMPETING CONTINUATION	$20,096
2009	2008	UNIVERSITY OF TOLEDO-HEALTH SCIENCE CAMPUS	3000 ARLINGTON AVENUE	TOLEDO	OH	43614	LUCAS	USA	Drug Use and Addiction Research Programs	001	17	12/5/2008	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$20,096
														Subtotal = $477,002

Issue Date FY: 2008 ( Subtotal = $358,313 )
2008	2008	UNIVERSITY OF TOLEDO-HEALTH SCIENCE CAMPUS	3000 ARLINGTON AVENUE	TOLEDO	OH	43614	LUCAS	USA	Drug Use and Addiction Research Programs	000	17	7/31/2008	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$176,462
2008	2008	BOSTON UNIVERSITY	25 BUICK STREET	BOSTON	MA	02215	SUFFOLK	USA	Drug Use and Addiction Research Programs	000	16	4/23/2008	NON-COMPETING CONTINUATION	$181,851
														Subtotal = $358,313

Issue Date FY: 2007 ( Subtotal = $365,625 )
2007	2007	BOSTON UNIVERSITY	25 BUICK STREET	BOSTON	MA	02215	SUFFOLK	USA	Drug Use and Addiction Research Programs	000	15	4/12/2007	COMPETING CONTINUATION	$365,625
														Subtotal = $365,625

Issue Date FY: 2004 ( Subtotal = $326,000 )
2004	2004	BOSTON UNIVERSITY	25 BUICK STREET	BOSTON	MA	02215	SUFFOLK	USA	Drug Use and Addiction Research Programs	000	14	8/24/2004	NON-COMPETING CONTINUATION	$326,000
														Subtotal = $326,000

Issue Date FY: 2003 ( Subtotal = $326,000 )
2003	2003	BOSTON UNIVERSITY	25 BUICK STREET	BOSTON	MA	02215	SUFFOLK	USA	Drug Use and Addiction Research Programs	000	13	5/30/2003	NON-COMPETING CONTINUATION	$326,000
														Subtotal = $326,000

Issue Date FY: 2002 ( Subtotal = $326,000 )
2002	2002	BOSTON UNIVERSITY	25 BUICK STREET	BOSTON	MA	02215	SUFFOLK	USA	Drug Use and Addiction Research Programs	000	12	5/21/2002	NON-COMPETING CONTINUATION	$326,000
														Subtotal = $326,000

Issue Date FY: 2001 ( Subtotal = $302,000 )
2001	2001	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Drug Use and Addiction Research Programs	000	10	6/6/2001	NON-COMPETING CONTINUATION	$302,000
														Subtotal = $302,000

Issue Date FY: 2000 ( Subtotal = $326,898 )
2000	2000	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Drug Use and Addiction Research Programs	000	9	8/28/2000	COMPETING CONTINUATION	$326,898
														Subtotal = $326,898

Issue Date FY: 1999 ( Subtotal = $229,230 )
1999	1999	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Drug Use and Addiction Research Programs	000	8	5/19/1999	NON-COMPETING CONTINUATION	$229,230
														Subtotal = $229,230

Issue Date FY: 1998 ( Subtotal = $220,413 )
1998	1998	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Drug Use and Addiction Research Programs	000	7	6/8/1998	NON-COMPETING CONTINUATION	$220,413
														Subtotal = $220,413

Grand Total All Awards = $5,589,448

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Methamphetamine Toxicity and Corticostriatal Glutamate

Award Number: R01DA007606

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/15/1992

PERIOD OF PERFORMANCE END DATE: 04/30/2017

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