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D1 DOPAMINE RECEPTOR SIGNALING AND COCAINE REINSTATEMENT

Award Number: R01DA022339
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/15/2008
PERIOD OF PERFORMANCE END DATE: 04/30/2013

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D1 DOPAMINE RECEPTOR SIGNALING AND COCAINE REINSTATEMENT - DESCRIPTION (provided by applicant): A growing body of evidence indicates that increases in dopamine and glutamate transmission in the nucleus accumbens independently promote the reinstatement of cocaine seeking, an animal model of relapse. The preliminary data presented in the current application demonstrate for the first time that cocaine reinstatement depends on interactions between accumbal shell dopamine and glutamate that are mediated by calcium/calmodulin-dependent protein kinase II (CaM-KII). Stimulation of D1-like (i.e. D1/D5) dopamine receptors in the nucleus accumbens shell reinstated cocaine seeking via the activation of L-type calcium channels. Reinstatement of cocaine seeking also was attenuated by injection of a CaM-KII inhibitor into the accumbens shell. Cocaine reinstatement was associated with increases in pCaM-KII and enhanced phosphorylation of GluR1 AMPA glutamate receptor subunits at S831, a site linked to CaM-KII-dependent trafficking of AMPA receptors to surface membranes. Finally, cocaine reinstatement was attenuated by intra- accumbal shell administration of a membrane-permeable form of Pep2-EVKI, a peptide that impairs AMPA receptor trafficking. Collectively, these results indicate that CaM-KII is a critical link between nucleus accumbens shell dopamine and glutamate systems involved in the neuronal plasticity underlying cocaine priming-induced reinstatement of drug seeking in rats. The current application will further examine the hypothesis that cocaine priming-induced reinstatement of cocaine seeking depends on the serial activation of D1-like dopamine receptors, PKA, L-type calcium channels and CaM-KII as well as the CaM-KII-dependent trafficking of AMPA receptor subunits to the synapse in the nucleus accumbens shell. Moreover, we propose to determine if similar or identical processes underlying cue-induced reinstatement of cocaine seeking. The experiments outlined in this proposal will define fundamental changes in D1-like dopamine receptor signaling that are associated with the reinstatement of cocaine seeking. The ultimate goal of these experiments is to identify novel targets for the development of pharmacotherapies for cocaine addiction. Our preliminary data indicate that L-type calcium channel and CaM-KII inhibitors as well as drugs that specifically influence AMPA receptor trafficking may be appropriate candidates for the treatment of cocaine addiction.The ultimate goal of these experiments is to identify novel targets for the development of drug therapies for cocaine craving and addiction. Using an animal model of cocaine craving, our preliminary data reveal that several classes of therapeutic drugs, including those that modulate dopamine and glutamate transmission in the brain, may be appropriate candidates for the treatment of cocaine 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: 2012 ( Subtotal = $341,807 )
2012	2012	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Drug Use and Addiction Research Programs	000	6	4/13/2012	NON-COMPETING CONTINUATION	$341,807
														Subtotal = $341,807

Issue Date FY: 2011 ( Subtotal = $348,855 )
2011	2011	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Drug Use and Addiction Research Programs	000	5	5/2/2011	NON-COMPETING CONTINUATION	$348,855
														Subtotal = $348,855

Issue Date FY: 2010 ( Subtotal = $352,378 )
2010	2010	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Drug Use and Addiction Research Programs	000	4	4/28/2010	NON-COMPETING CONTINUATION	$352,378
														Subtotal = $352,378

Issue Date FY: 2009 ( Subtotal = $355,938 )
2009	2009	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Drug Use and Addiction Research Programs	002	3	4/22/2009	NON-COMPETING CONTINUATION	$355,938
2009	2008	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Drug Use and Addiction Research Programs	001	2	2/5/2009	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$371,563
2009	2008	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Drug Use and Addiction Research Programs	000	1	2/5/2009	NEW	-$371,563
														Subtotal = $355,938

Issue Date FY: 2008 ( Subtotal = $371,563 )
2008	2008	BOSTON UNIVERSITY	25 BUICK STREET	BOSTON	MA	02215	SUFFOLK	USA	Drug Use and Addiction Research Programs	000	1	5/14/2008	NEW	$371,563
														Subtotal = $371,563

Grand Total All Awards = $1,770,541

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D1 DOPAMINE RECEPTOR SIGNALING AND COCAINE REINSTATEMENT

Award Number: R01DA022339

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/15/2008

PERIOD OF PERFORMANCE END DATE: 04/30/2013

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