Cocaine abuse in the United States is a major public health concern. Cocaine use leads to activation of specific circuits in the brain, most notably mesolimbic dopamine neurons. With continued use, neuroadaptive changes occur in these neurons which lead to even more protracted use of the drug. Significant progress has been made in the elucidation of the biochemical mechanisms underlying the neuroadaptive changes, however, the regulation of gene transcription by cocaine in human post-mortem tissue has received considerably less attention.
The first aim will compare regional gene expression between the ventral tegmental area (VTA) versus lateral substantial nigra (l-SN) and nucleus accumbens (NAc) versus dorsal caudate-putamen (d-CP) in post-mortem tissue from cocaine overdose victims and age-matched, non-drug controls. Based on preliminary data, we predict chronic cocaine use is preferentially associated with altered expression of genes encoding dopamine- and signal transduction-related proteins in the VTA and NAc compared with the l-SN and d-CP, respectively. In the second aim, we will examine the gene expression in a discrete neuronal population by comparing profiles of tyrosine hydroxylase immuno-positive neurons in the VTA and 1-SN between cocaine overdose victims and controls. To this end, we predict preferentially altered expression of genes encoding dopamine- and signal transduction-related proteins in dopamine neurons in the VTA compared with the l-SN in cocaine overdose victims.
This aim i s based on the idea that coordinate dysregulation of several genes in discrete neuronal populations is linked to cocaine abuse. Results from these studies will provide correlative evidence of the involvement of multiple transcripts and a detailed expression profile of human cocaine abuse.
The final aim i s to evaluate changes in protein levels and function associated with the expression profile of genes, in particular dopamine related and signal transduction-related proteins. The application will utilize human post-mortem tissue and state-of-the-art regional and single neuron expression and cDNA array methodologies to provide the first extensive expression profile of cocaine addiction. Characterization of altered expression patterns for thousands of genes will provide a panoramic view of the potential molecular underpinnings of cocaine reinforcement and the neuroadaptive changes in these neurons associated with long-term use. In addition, identification of differentially expressed genes may provide novel targets for the pharmacotherapeutic development and/or the refinement of existent pharmacotherapies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA013772-03
Application #
6665383
Study Section
Special Emphasis Panel (ZRG1-SSS-Q (01))
Program Officer
Rutter, Joni
Project Start
2001-09-15
Project End
2004-08-31
Budget Start
2003-09-01
Budget End
2004-08-31
Support Year
3
Fiscal Year
2003
Total Cost
$353,216
Indirect Cost
Name
Emory University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Tannu, N; Mash, D C; Hemby, S E (2007) Cytosolic proteomic alterations in the nucleus accumbens of cocaine overdose victims. Mol Psychiatry 12:55-73
Tannu, Nilesh; Hemby, Scott E (2006) Quantitation in two-dimensional fluorescence difference gel electrophoresis: effect of protein fixation. Electrophoresis 27:2011-5
Tannu, Nilesh S; Hemby, Scott E (2006) Two-dimensional fluorescence difference gel electrophoresis for comparative proteomics profiling. Nat Protoc 1:1732-42
Hemby, Scott E (2006) Assessment of genome and proteome profiles in cocaine abuse. Prog Brain Res 158:173-95
O'Connor, Joann; Muly, Emil C; Hemby, Scott E (2006) Molecular mapping of striatal subdivisions in juvenile Macaca Mulata. Exp Neurol 198:326-37
Smith, James E; Co, Conchita; Coller, Michael D et al. (2006) Self-administered heroin and cocaine combinations in the rat: additive reinforcing effects-supra-additive effects on nucleus accumbens extracellular dopamine. Neuropsychopharmacology 31:139-50
Hemby, Scott E; Tang, Wenxue; Muly, Emil C et al. (2005) Cocaine-induced alterations in nucleus accumbens ionotropic glutamate receptor subunits in human and non-human primates. J Neurochem 95:1785-93
Hemby, Scott E; Horman, Brian; Tang, Wenxue (2005) Differential regulation of ionotropic glutamate receptor subunits following cocaine self-administration. Brain Res 1064:75-82
Freeman, W M; Brebner, K; Amara, S G et al. (2005) Distinct proteomic profiles of amphetamine self-administration transitional states. Pharmacogenomics J 5:203-14
Freeman, Willard M; Hemby, Scott E (2004) Proteomics for protein expression profiling in neuroscience. Neurochem Res 29:1065-81

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