Mammalian brain dopamine system is a critical modulator of a wide variety of brain functions, including movement control, reward and motivation, thought process, and learning and memory. Psychoactive drugs cocaine and amphetamine act through the brain dopamine system, and wide-spread drug abuse is a major concern in our society. Understanding the molecular mechanisms underlying dopamine system signal transduction which modulate various brain functions in both normal and drug stimulated states is crucial for developing methods for the prevention and treatment of drug abuse. D1 dopamine receptor is highly expressed and widely distributed in the brain. Stimulation of D1 receptor has been shown to couple to multiple second messenger systems in transfected cells and is necessary for locomotor stimulant effect of cocaine. However, the molecular mechanisms and the regulation of D1 receptor signaling in normal and cocaine treated brains are unclear. Our working hypothesis is that multiple D1 dopamine receptor-interacting proteins are involved in both the signal transduction from the D1 receptor, and the regulation of the signal transduction process. The scope of this proposal is to use a novel molecular approach, the yeast two-hybrid system, to identify genes encoding the D1 receptor-interacting proteins. We will study the roles of these genes in D1 receptor signaling in transfected cells, and investigate the expression of these genes in both wild-type and D1 receptor knockout mice. Furthermore, we will study the expression of these genes in both of these mice upon cocaine treatments. The completion of these studies may lead to new insights into the mechanisms of dopaminergic signal transduction and new approaches for potential treatment of drug abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29DA011284-05
Application #
6378705
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Lin, Geraline
Project Start
1997-08-15
Project End
2002-07-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
5
Fiscal Year
2001
Total Cost
$108,420
Indirect Cost
Name
University of Cincinnati
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Caine, S Barak; Thomsen, Morgane; Gabriel, Kara I et al. (2007) Lack of self-administration of cocaine in dopamine D1 receptor knock-out mice. J Neurosci 27:13140-50
McNamara, Robert K; Logue, Aaron; Stanford, Kevin et al. (2006) Dose-response analysis of locomotor activity and stereotypy in dopamine D3 receptor mutant mice following acute amphetamine. Synapse 60:399-405
McQuade, Jill M Slane; Tamashiro, Kellie L K; Wood, Gwendolyn E et al. (2006) Deficient hippocampal c-fos expression results in reduced anxiety and altered response to chronic stress in female mice. Neurosci Lett 403:125-30
Zhang, Dongsheng; Zhang, Lu; Tang, Yang et al. (2005) Repeated cocaine administration induces gene expression changes through the dopamine D1 receptors. Neuropsychopharmacology 30:1443-54
Zhang, Lu; Lou, Danwen; Jiao, Hongyuan et al. (2004) Cocaine-induced intracellular signaling and gene expression are oppositely regulated by the dopamine D1 and D3 receptors. J Neurosci 24:3344-54
Wu, Yongfei; Zhang, Dongsheng; Lou, Danwen et al. (2004) C-fos regulates neuropeptide Y expression in mouse dentate gyrus. Neurosci Lett 363:6-10
Zheng, Wei; Xie, Wenrui; Zhang, Jianhua et al. (2003) Function of gamma-aminobutyric acid receptor/channel rho 1 subunits in spinal cord. J Biol Chem 278:48321-9
Zhang, Jianhua; Zhang, Dongsheng; Xu, Ming (2002) Identification of chronic cocaine-induced gene expression through dopamine d1 receptors by using cDNA microarrays. Ann N Y Acad Sci 965:1-9
Slane McQuade, Jill M; Vorhees, Charles V; Xu, Ming et al. (2002) DNA fragmentation factor 45 knockout mice exhibit longer memory retention in the novel object recognition task compared to wild-type mice. Physiol Behav 76:315-20
Zhang, Dongsheng; Zhang, Lu; Lou, Dan Wen et al. (2002) The dopamine D1 receptor is a critical mediator for cocaine-induced gene expression. J Neurochem 82:1453-64

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