This application proposes to investigate the function and role(s) of NAC-1. NAC-1 is a member of the POZ family of proteins and is present in the mammalian central nervous system (CNS). NAC-1 mRNA levels are increased in the nucleus accumbens of the rat CNS three weeks after chronic cocaine self administration. Interruption of NAC-1 expression via microinjection of antisense oligonucleotides into the rat nucleus accumbens augmented the locomotor responses to acute and chronic treatment, supporting the hypothesis that NAC-1 regulates the function of neurons in the nucleus accumbens that contribute to the behavioral sensitization and cocaine self-administration. The proposed molecular and behavioral studies are designed to understand how alterations in NAC-1 expression affect cocaine associated behaviors.
The Specific Aims will:
Aim 1 : study NAC-1 binding to specific DNA sequences and other proteins and examine the effects of cocaine treatment on these interactions in the CNS;
Aim 2 : demonstrate the intracellular location (in vitro studies) and regional CNS distribution (in vivo studies) of NAC-1 protein before and after cocaine treatment;
Aim 3 : study the effects of diminished NAC-1 levels in the nucleus accumbens on the behavioral effects of acute cocaine and cocaine self- administration in the rat. Motor behavior or the rate of reinstatement of self administration will be measured after antisense oligonucleotide injection;
Aim 4 : determine the behavioral effects of acute cocaine after over- expression of NAC-1 protein in the nucleus accumbens via injection of a recombinant adeno virus vector that contains the NAC-1 cDNA. Repeated cocaine use leads to persistent molecular and behavioral changes. NAC-1 is one mRNA that demonstrates a long-term adaptation to cocaine use. Results from studies of NAC-1 function in the rat may be helpful in future studies of human subjects who abuse cocaine.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA011809-04
Application #
6497811
Study Section
Special Emphasis Panel (ZRG1-IFCN-1 (02))
Program Officer
Satterlee, John S
Project Start
1999-03-15
Project End
2003-04-14
Budget Start
2002-04-01
Budget End
2003-04-14
Support Year
4
Fiscal Year
2002
Total Cost
$369,217
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
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

Showing the most recent 10 out of 17 publications