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INTERACTIONS BETWEEN CB1 RECEPTOR AND DA RECEPTORS IN THE NUCLEUS ACCUMBENS CORE

Award Number: F32DA028065
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2010
PERIOD OF PERFORMANCE END DATE: 06/30/2013

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INTERACTIONS BETWEEN CB1 RECEPTOR AND DA RECEPTORS IN THE NUCLEUS ACCUMBENS CORE - 6. Project Summary/Abstract A vast literature has shown that dopamine (DA) signaling in the nucleus accumbens (NAc) is a critical mediator of addiction-related and goal-directed behaviors. Thus, there is considerable interest in understanding the molecular mechanisms through which DA can alter the NAc firing activity and modulate behavior. Previous studies from the Bonci lab found that cooperative activation of DA D1 and D2 receptors increases firing of NAc neurons. Interestingly, many motivated and addiction-related behaviors are sustained by activity of both D1 and D2 receptors in the NAc. Further, cannabinoid type-1 (CB1) receptors in the NAc can also critically regulate motivated behavior. Thus, the main goal of this proposal is to use in vitro techniques, in particular whole-cell patch-clamp electrophysiology in NAc brain slices prepared from adult male rats to understand the molecular mechanisms through which endogenous cannabinoids (eCBs) and CB1 receptor activity could interact with dopamine receptors to enhance NAc firing activity. The long-term goal is to understand how NAcore CB1 and dopamine receptors interact to drive adaptive as well as pathological motivated behaviors, with the hope of developing novel therapeutic interventions for human neurological conditions. My preliminary data indicate that CB1 receptor antagonists prevent the D1/D2 cooperative enhancement of NAc core firing, suggesting that eCB activation of CB1 receptors could play a critical role in this process. However, the cellular mechanisms through which this occurs, especially the type of eCB which might contribute, remain unknown. Specific Aim ¿ will examine the contribution of CB1 receptors to the D1/D2-mediated enhancement in NAc core firing. The role of CB1 receptors will be determined with several different CB1 receptor antagonists. The contribution of CB1 receptors will also be examined by investigating whether CB1 receptor activators can enhance NAc core firing alone, or whether interaction with a D1 or D2 receptor agonist is required to enhance firing. Specific Aim ¿¿ will investigate intracellular pathways through which CB1 receptor activation could facilitates NAc core firing. In particular, the identify of the eCB which mediates the CB1/D1/D2 interaction will be examined using inhibitors of PLC, an enzyme critical for several eCB synthesis pathways, and inhibitors of FAAH and MGL, which hydrolyze the eCBs AEA and 2-AG. Also, neurons will be filled with AEA or 2-AG to determine whether these eCBs can increase NAc core firing alone or in combination with D1 or D2 receptor agonists. Together, these experiments will provide important information about the eCB that contributes critically to the D1/D2-mediated enhancement in NAc firing and the possible mechanism(s) through which dopamine and CB1 receptors could interact to enhance NAc firing activity. To facilitate achieving these goals, I will receive ongoing training and mentoring from my sponsor, other lab members, and outside collaborators in the design, implementation, and interpretation of my experiments, in the relevant research literature, and the preparation of my results for submission for publication.


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: 2013 ( Subtotal = -$7,970 )
2013	2012	ERNEST GALLO CLINIC & RESEARCH CENTER	5858 HORTON STREET, SUITE 200	EMERYVILLE	CA	94608	ALAMEDA	USA	Drug Use and Addiction Research Programs	000	3	8/13/2013	NON-COMPETING CONTINUATION	-$7,970
														Subtotal = -$7,970

Issue Date FY: 2012 ( Subtotal = $55,670 )
2012	2012	ERNEST GALLO CLINIC & RESEARCH CENTER	5858 HORTON STREET, SUITE 200	EMERYVILLE	CA	94608	ALAMEDA	USA	Drug Use and Addiction Research Programs	000	3	8/14/2012	NON-COMPETING CONTINUATION	$55,670
														Subtotal = $55,670

Issue Date FY: 2011 ( Subtotal = $53,042 )
2011	2011	ERNEST GALLO CLINIC & RESEARCH CENTER	5858 HORTON STREET, SUITE 200	EMERYVILLE	CA	94608	ALAMEDA	USA	Drug Use and Addiction Research Programs	000	2	7/29/2011	NON-COMPETING CONTINUATION	$53,042
														Subtotal = $53,042

Issue Date FY: 2010 ( Subtotal = $50,474 )
2010	2010	ERNEST GALLO CLINIC & RESEARCH CENTER	5858 HORTON STREET, SUITE 200	EMERYVILLE	CA	94608	ALAMEDA	USA	Drug Use and Addiction Research Programs	000	1	9/1/2010	NEW	$0
2010	2010	ERNEST GALLO CLINIC & RESEARCH CENTER	5858 HORTON STREET, SUITE 200	EMERYVILLE	CA	94608	ALAMEDA	USA	Drug Use and Addiction Research Programs	001	1	9/1/2010	NEW	$50,474
														Subtotal = $50,474

Grand Total All Awards = $151,216

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INTERACTIONS BETWEEN CB1 RECEPTOR AND DA RECEPTORS IN THE NUCLEUS ACCUMBENS CORE

Award Number: F32DA028065

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2010

PERIOD OF PERFORMANCE END DATE: 06/30/2013

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