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FINE MAPPING GENES FOR COCAINE LOCOMOTOR RESPONSE IN ENU MUTAGENIZED MICE

Award Number: R01DA022392
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2007
PERIOD OF PERFORMANCE END DATE: 05/31/2011

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FINE MAPPING GENES FOR COCAINE LOCOMOTOR RESPONSE IN ENU MUTAGENIZED MICE - DESCRIPTION (provided by applicant): Vulnerability to develop addiction to psychostimulants, including cocaine and amphetamine, as well as other drugs, like alcohol, is influenced by both genetic and environmental factors. Genetic factors may modulate differing initial responses to drugs of abuse in humans and this has been linked to the propensity to develop a drug abuse disorder. Abnormal adaptations in stress response pathways have also been implicated in the development of drug dependence and while this relationship is firmly established, the underlying neurobiological mechanisms are not well understood. While no animal model exists that reproduces the entire spectrum of the drug abuse syndrome in humans, animal models do exist for certain drug-related behaviors including acute locomotor activation, behavioral sensitization and conditioned place preference in response to drug treatment, as well as rates of drug self-administration. We have identified an ENU-induced mutant, Highper, that shows hyperlocomotion in a novel environment, an exaggerated locomotor response to the psychostimulants cocaine and methylphenidate and a prolonged release of corticosterone following an acute stressor. We believe that the abnormal stress and drug responses exhibited by these animals are related; our hypothesis is that the exaggerated locomotor response to psychostimulants is exacerbated by previous exposure to stressful events. Using single nucleotide polymorphism (SNP) genotyping, we have mapped the Highper mutation to a 59 megabase region on chromosome 12. This region contains 411 genes, none of which has previously been implicated in both drug and stress responses. Thus, Highper may represent a novel model for studying the relationship between the stress and drug response behavioral domains. In this proposal, we outline an experimental strategy to address our three primary goals: 1) to further characterize the Highper line to better understand the abnormal stress and psychostimulant responses and the link between the two 2) to fine map and identify the causative mutation and 3) to characterize the functional disruption caused by the gene mutation both in vivo and in vitro.


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: 2010 ( Subtotal = $175,096 )
2010	2010	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Drug Use and Addiction Research Programs	000	5	5/25/2010	NON-COMPETING CONTINUATION	$175,096
														Subtotal = $175,096

Issue Date FY: 2009 ( Subtotal = $355,715 )
2009	2009	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Drug Use and Addiction Research Programs	000	4	5/19/2009	NON-COMPETING CONTINUATION	$355,715
														Subtotal = $355,715

Issue Date FY: 2008 ( Subtotal = $355,715 )
2008	2008	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Drug Use and Addiction Research Programs	000	3	6/26/2008	NON-COMPETING CONTINUATION	$355,715
														Subtotal = $355,715

Issue Date FY: 2007 ( Subtotal = $375,000 )
2007	2007	GENOMICS INSTITUTE OF THE NOVARTIS RESEARCH FOUNDATION	10675 JOHN JAY HOPKINS DRIVE	SAN DIEGO	CA	92121	SAN DIEGO	USA	Drug Use and Addiction Research Programs	000	1	8/24/2007	NEW	$375,000
														Subtotal = $375,000

Grand Total All Awards = $1,261,526

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FINE MAPPING GENES FOR COCAINE LOCOMOTOR RESPONSE IN ENU MUTAGENIZED MICE

Award Number: R01DA022392

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2007

PERIOD OF PERFORMANCE END DATE: 05/31/2011

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