Drug addiction is associated with long-term behavioral changes. Identifying molecules that contribute to these behaviors is an important goal. NAC1 is a member of the POZ/BTB family of transcription factors that demonstrated increases in gene expression weeks after cocaine self-administration in the rat. Manipulation of NAC 1 levels in the rat nucleus accumbens caused changes in cocaine-regulated behaviors, yet the endogenous function of NAC 1 remains unknown. The proposed molecular and behavioral studies are designed to examine the role of NACI in the mammaliml brain and NAC1 's impact on cocaine-induced-behaviors.
The specific aims will demonstrate:
Aim 1. where NACI is expresseEand how cocaine administration will affect NAC1 's distribution; Immunokigtology will be performed using a polyclonal antibody that detects which cellular nuclei contain NAC 1 and the expression pattern will be determined in those CNS regions known to be involved in cocaine-induced behaviors.
Aim 2. what other proteins interact with NAC1; Both POZ-BTB and non-OZ BTB proteins will be examined for their interactions with NAC 1. NAC 1, either full-length or in truncated forms, will be used as the """"""""bait"""""""" to screen a mouse brain library, using a yeast two-hybrid screen. The protein-protein interactions will be confirmed by several biochemical tests and each cDNA will be sequenced to determine the identity of the encoded protein.
Aim 3. the effects of manipulating NAC1 gene expression? Mice will be bred which do not express NAC1. They will be examined for: their phenotype and the behavioral responses to cocaine. The characterization of NAC 1, a gene that eMaibited long-term changes in expression after cocaine use, will further the understanding of cocaine addiction. The hnman NAC 1 proteinis similar to that of rat and mouse, therefore these experiments may provide important insights into cocaine abuse in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA011809-06
Application #
6734610
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Satterlee, John S
Project Start
1999-03-15
Project End
2006-02-28
Budget Start
2004-03-01
Budget End
2005-02-28
Support Year
6
Fiscal Year
2004
Total Cost
$416,036
Indirect Cost
Name
University of Pennsylvania
Department
Pharmacology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Scofield, M D; Korutla, L; Jackson, T G et al. (2012) Nucleus Accumbens 1, a Pox virus and Zinc finger/Bric-a-brac Tramtrack Broad protein binds to TAR DNA-binding protein 43 and has a potential role in Amyotrophic Lateral Sclerosis. Neuroscience 227:44-54
Uys, Joachim D; Knackstedt, Lori; Hurt, Phelipe et al. (2011) Cocaine-induced adaptations in cellular redox balance contributes to enduring behavioral plasticity. Neuropsychopharmacology 36:2551-60
Korutla, Laxminarayana; Wang, Peijie; Jackson, Trevor G et al. (2009) NAC1, a POZ/BTB protein that functions as a corepressor. Neurochem Int 54:245-52
Mackler, Scott; Pacchioni, Alejandra; Degnan, Ryan et al. (2008) Requirement for the POZ/BTB protein NAC1 in acute but not chronic psychomotor stimulant response. Behav Brain Res 187:48-55
Korutla, Laxminarayana; Degnan, Ryan; Wang, Peijie et al. (2007) NAC1, a cocaine-regulated POZ/BTB protein interacts with CoREST. J Neurochem 101:611-8
Kalivas, Peter W (2007) Cocaine and amphetamine-like psychostimulants: neurocircuitry and glutamate neuroplasticity. Dialogues Clin Neurosci 9:389-97
Shen, Haowei; Korutla, Laxminarayana; Champtiaux, Nicholas et al. (2007) NAC1 regulates the recruitment of the proteasome complex into dendritic spines. J Neurosci 27:8903-13
Stromberg, Michael F; Mackler, Scott A (2005) The effect of cocaine on the expression of motor activity and conditioned place preference in high and low alcohol-preferring Wistar rats. Pharmacol Biochem Behav 82:314-9
Korutla, L; Wang, P J; Mackler, S A (2005) The POZ/BTB protein NAC1 interacts with two different histone deacetylases in neuronal-like cultures. J Neurochem 94:786-93
Korutla, Laxman; Champtiaux, Nicholas; Shen, Hao-Wei et al. (2005) Activity-dependent subcellular localization of NAC1. Eur J Neurosci 22:397-403

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