The Nucleus Accumbens (NAc) is implicated in craving, reward and reinforcement of alcohol drinking. The NAc/Striatum expresses the highest levels of high affinity adenosine A2A receptors in the central nervous system (CNS) and is characterized by co-expression of A2A with dopamine D2 receptors (D2) on the same neurons. We have evidence that subthreshold concentrations of the D2 agonist NPA and ethanol, that have no effect alone, act synergistically when added together to stimulate PKA signaling. Synergy requires bettayamma, dimers and A2 receptors. Neurons that express D2 and A2 on the same cells, as in the NAc, are simultaneously hypersensitive to ethanol in the presence of dopaminergic tone and hypersensitive to D2 signaling in the presence of ethanol. Synergy may play a role in ethanol consumption. Expression of a beta/gamma, inhibitor in NAc reduces voluntary ethanol consumption. Our hypothesis is that unique and specific signaling components are responsible for synergy between D2 and ethanol/A2 in NAc/striatal neurons and that these molecules regulate drinking behaviors. The overall goal of this project is (a) to identify the specific molecular signaling components in NAc/Striatal neurons which regulate ethanol-induced increases in PKA signaling and reinforcement of ethanol consumption, and, (b) to develop new therapeutics for alcoholism.
Our specific aims are: I: Identify specific G-protein components responsible for synergy between ethanol and NPA for activation of PKA signaling; Il: Test whether a specific activator of G protein signaling, AGS3, selectively regulates synergy between D2 and ethanol; III: Test which specific beta/gamma dimers released upon D2 activation activate adenylyl cyclase II and/or IV in primary striatal neurons; and IV: Test the role of the ethanol/A2 and D2 signaling components in ethanol operant self-administration and in CNS responses to ethanol. The experiments in this proposal will identify and validate novel targets for the development of new therapeutic agents to treat alcoholism and alcohol abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA010030-14
Application #
7434535
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Twombly, Dennis
Project Start
2005-09-01
Project End
2010-05-31
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
14
Fiscal Year
2008
Total Cost
$491,808
Indirect Cost
Name
Cv Therapeutics, Inc.
Department
Type
DUNS #
796248110
City
Palo Alto
State
CA
Country
United States
Zip Code
94304
Fan, Peidong; Jiang, Zhan; Diamond, Ivan et al. (2009) Up-regulation of AGS3 during morphine withdrawal promotes cAMP superactivation via adenylyl cyclase 5 and 7 in rat nucleus accumbens/striatal neurons. Mol Pharmacol 76:526-33
Yao, Lina; Fan, Peidong; Jiang, Zhan et al. (2008) Dopamine and ethanol cause translocation of epsilonPKC associated with epsilonRACK: cross-talk between cAMP-dependent protein kinase A and protein kinase C signaling pathways. Mol Pharmacol 73:1105-12
Asyyed, Asma; Storm, Daniel; Diamond, Ivan (2006) Ethanol activates cAMP response element-mediated gene expression in select regions of the mouse brain. Brain Res 1106:63-71
Yao, Lina; McFarland, Krista; Fan, Peidong et al. (2005) Activator of G protein signaling 3 regulates opiate activation of protein kinase A signaling and relapse of heroin-seeking behavior. Proc Natl Acad Sci U S A 102:8746-51
Arolfo, Maria Pia; Yao, Lina; Gordon, Adrienne S et al. (2004) Ethanol operant self-administration in rats is regulated by adenosine A2 receptors. Alcohol Clin Exp Res 28:1308-16
Souroujon, Miriam C; Yao, Lina; Chen, Haibin et al. (2004) State-specific monoclonal antibodies identify an intermediate state in epsilon protein kinase C activation. J Biol Chem 279:17617-24
Mailliard, William S; Diamond, Ivan (2004) Recent advances in the neurobiology of alcoholism: the role of adenosine. Pharmacol Ther 101:39-46
Yao, Lina; Fan, Peidong; Jiang, Zhan et al. (2003) Addicting drugs utilize a synergistic molecular mechanism in common requiring adenosine and Gi-beta gamma dimers. Proc Natl Acad Sci U S A 100:14379-84
Yao, Lina; Arolfo, Maria Pia; Dohrman, Douglas P et al. (2002) betagamma Dimers mediate synergy of dopamine D2 and adenosine A2 receptor-stimulated PKA signaling and regulate ethanol consumption. Cell 109:733-43
Dohrman, Douglas P; Chen, Hui-min; Gordon, Adrienne S et al. (2002) Ethanol-induced translocation of protein kinase A occurs in two phases: control by different molecular mechanisms. Alcohol Clin Exp Res 26:407-15

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