Addiction is associated with long-term behavioral changes produced by repeated exposure to drugs of abuse. The enduring nature of addiction implies equally enduring changes in brain biochemistry. Identifying molecules that contribute to enduring behavioral changes elicited by addictive drugs may provide novel pharmacotherapeutic targets for treating addiction. During the previous tenure of this application NAC1 was characterized as a member of the POZ/BTB family of transcription factors that demonstrates increases in gene expression in the nucleus accumbens weeks after discontinuing cocaine self-administration in rats. Using antisense oligonucleotide and viral transfection strategies, the level of NAC1 in the rat nucleus accumbens was shown to be inversely related to the expression of locomotor sensitization elicited by repeated cocaine administration. However, the physiological function of endogenous NAC1 remains unknown. This application will examine the physiological role of NAC1 in the mammalian brain and its potential pathological role in cocaine-induced behaviors. It is proposed to examine the role of NAC1 as a transcriptional regulator, and as a proteasome binding partner in protein degradation. The relevance of these functions in cocaine addiction will be examined in vivo, using AAV transfection of NAC1 cDNA or siRNA and animals models of cocaine-induced behavioral plasticity and addiction, such as locomotor sensitization and the reinstatement of drug-seeking. The overall hypothesis of this application is that the regulation of NAC1 by withdrawal from cocaine is an important compensatory physiological response consisting of changes in gene transcription and mobilization of proteasome activity.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Molecular Neuropharmacology and Signaling Study Section (MNPS)
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Wu, Da-Yu
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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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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