The mesolimbic dopamine (DA) system has been primarily implicated in the reinforcing effects of drugs of abuse. While this pathwayand DA signaling are the focus of most research in this area, it is also clear that norepinephrine (NE), via interactions with the dopaminergic system, plays an important role in modulating the neurochemical and behavioral responses to drugs of abuse in animal models. The enzyme dopamine (3-hydroxylase(DBH) converts DA to NE in noradrenegic cells, thus controlling the abundanceof both NE and DA in the brain. Genetic and pharmacological data in humans support an important role for DBH in modulating psychostimulant-related behaviors. First, a common polymorphism in the humanDbh gene is a critical determinant of DBH enzymatic activity and appears to influence behavioral andcognitive responses to cocaine. Second, the DBH inhibitor disulfiram (Antabuse) has shown striking promise as a treatment for cocaine dependence, yet its mechanism of action is unknown. The objective of this proposal is to determine the influence of DBHactivity on catecholamine neurochemistry and cocaine-related behaviors, including sensitization, reward, aversion, and relapse, and to understand why disulfiram administration results in cocaine abstinence in dependent humans. This will be accomplished by using a combination of genetics (Dbh knockout mice), and pharmacology (disulfiram). Completion of the aims in this proposalwill contribute to our understanding of how the interaction between noradrenergic and dopaminergic systemsinfluences drug addiction and the mechanism of disulfiram- induced cocaine abstinence, and will suggest novel treatments for psychostimulant dependence.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA017963-04
Application #
7587415
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Volman, Susan
Project Start
2006-04-10
Project End
2010-09-30
Budget Start
2009-04-01
Budget End
2010-09-30
Support Year
4
Fiscal Year
2009
Total Cost
$326,224
Indirect Cost
Name
Emory University
Department
Genetics
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Gaval-Cruz, Meriem; Goertz, Richard B; Puttick, Daniel J et al. (2016) Chronic loss of noradrenergic tone produces ?-arrestin2-mediated cocaine hypersensitivity and alters cellular D2 responses in the nucleus accumbens. Addict Biol 21:35-48
Schmidt, Karl T; Weinshenker, David (2014) Adrenaline rush: the role of adrenergic receptors in stimulant-induced behaviors. Mol Pharmacol 85:640-50
Cooper, Debra A; Kimmel, Heather L; Manvich, Daniel F et al. (2014) Effects of pharmacologic dopamine ?-hydroxylase inhibition on cocaine-induced reinstatement and dopamine neurochemistry in squirrel monkeys. J Pharmacol Exp Ther 350:144-52
Mitrano, Darlene A; Schroeder, Jason P; Smith, Yoland et al. (2012) ?-1 Adrenergic receptors are localized on presynaptic elements in the nucleus accumbens and regulate mesolimbic dopamine transmission. Neuropsychopharmacology 37:2161-72
Gaval-Cruz, Meriem; Liles, Larry Cameron; Iuvone, Paul Michael et al. (2012) Chronic inhibition of dopamine ýý-hydroxylase facilitates behavioral responses to cocaine in mice. PLoS One 7:e50583
Keebaugh, Alaine C; Mitchell, Heather A; Gaval-Cruz, Meriem et al. (2011) PRTFDC1 is a genetic modifier of HPRT-deficiency in the mouse. PLoS One 6:e22381
Lee, Sarah Emerson; Simons, Stephen B; Heldt, Scott A et al. (2010) RGS14 is a natural suppressor of both synaptic plasticity in CA2 neurons and hippocampal-based learning and memory. Proc Natl Acad Sci U S A 107:16994-8
Mitchell, Heather A; Weinshenker, David (2010) Good night and good luck: norepinephrine in sleep pharmacology. Biochem Pharmacol 79:801-9
Schroeder, Jason P; Cooper, Debra A; Schank, Jesse R et al. (2010) Disulfiram attenuates drug-primed reinstatement of cocaine seeking via inhibition of dopamine ?-hydroxylase. Neuropsychopharmacology 35:2440-9
Gaval-Cruz, Meriem; Weinshenker, David (2009) mechanisms of disulfiram-induced cocaine abstinence: antabuse and cocaine relapse. Mol Interv 9:175-87

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