Cocaine and amphetamine are powerful psychomotor stimulants and widespread abuse of these drugs creates a major problem in the society. Understanding the molecular mechanisms underlying the behavioral and neuroplastic changes caused by cocaine and amphetamine is crucial for developing methods of the prevention and treatment of drug abuse. It has been demonstrated that the acute actions of these psychostimulants depend on the potentiation of dopamine neurotransmission in the mesolimbic dopamine pathway, particularly through the D1 dopamine receptors. However, little is known regarding the intracellular events mediating the effects of these psychostimulants. Immediate early gene c-fos encodes a transcription factor and is induced through the D1 dopamine receptors by both cocaine and amphetamine. Our hypothesis is that c-fos is necessary in mediating both the locomotor stimulating and positive reinforcing effects of cocaine and amphetamine, and in AP-1 transcription complex formation in response to acute cocaine treatments. We propose to use the conditional gene targeting technology and generate mice with forebrain mutation of c-fos. We propose to test the above hypothesis in these mutant mice using behavioral, biochemical and histological methods. The successful completion of the proposed project will allow us to determine the role of c-fos in mediating the acute actions of psychostimulants and provide basis for investigating its role in the chronic effects of these drugs, and for finding possible target genes involved in drug addiction in the future.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29DA011005-03
Application #
2898129
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Pollock, Jonathan D
Project Start
1997-05-01
Project End
2002-03-31
Budget Start
1999-04-10
Budget End
2000-03-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Dong, Mei; Wu, Yongfei; Fan, Yunxia et al. (2006) c-fos modulates brain-derived neurotrophic factor mRNA expression in mouse hippocampal CA3 and dentate gyrus neurons. Neurosci Lett 400:177-80
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
Wu, Yongfei; Dong, Mei; Toepfer, Nicholas J et al. (2004) Role of endonuclease G in neuronal excitotoxicity in mice. Neurosci Lett 364:203-7
Wu, Yongfei; Zhang, Dongsheng; Lou, Danwen et al. (2004) C-fos regulates neuropeptide Y expression in mouse dentate gyrus. Neurosci Lett 363:6-10
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
Jin, Wenzhen; Zhang, Jianhua; Lou, Danwen et al. (2002) C-fos-deficient mouse hippocampal CA3 pyramidal neurons exhibit both enhanced basal and kainic acid-induced excitability. Neurosci Lett 331:151-4
Zhang, J; Xu, M (2001) Toward a molecular understanding of psychostimulant actions using genetically engineered dopamine receptor knockout mice as model systems. J Addict Dis 20:7-18
Zhang, J; Lee, H; Agarwala, A et al. (2001) Dna fragmentation factor 45 mutant mice exhibit resistance to kainic acid-induced neuronal cell death. Biochem Biophys Res Commun 285:1143-9

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