Inhibiting activator protein-1 activity alters cocaine-induced gene expression and potentiates sensitization

Abstract

We have expressed A-FOS, an inhibitor of AP-1 DNA binding, in adult mouse striatal neurons. We observe normal behavior including locomotion and exploratory activities. Following a single injection of cocaine, locomotion increased similarly in both the A-FOS expressing and littermate controls. However, following repeated injections of cocaine, the A-FOS expressing mice showed increased locomotion relative to littermate controls, an increase that persisted following a week of withdrawal and subsequent cocaine administration. These results indicate that AP-1 suppresses this behavioral responses to cocaine. We analyzed mRNA from the striatum before and 4 and 24 hours after a single cocaine injection in both A-FOS and control striata using Affymetrix microarrays (430 2.0 Array) to identify genes mis-regulated by A-FOS that may mediate the increased locomotor sensitization to cocaine. A-FOS expression did not change gene expression in the basal state or 4 hours following cocaine treatment relative to controls. However, 24 hours after an acute cocaine treatment, 84 genes were identified that were differentially expressed between the A-FOS and control mice. 56 gene are down regulated while 28 genes are up regulated including previously identified candidates for addiction including BDNF and Per1. Using a random sample of identified genes, quantitative PCR was used to verify the microarray studies. The chromosomal location of these 84 genes was compared to human genome scans of addiction to identify potential genes in humans that are involved in addiction. Keywords A-FOS; addiction; sensitization; gene expressionPsychostimulants can produce a persistent state of compulsive drug use known as addiction. Although, there is much evidence that both the rewarding and addictive properties of these *To whom correspondence should be addressed. Laboratory of Metabolism, National Cancer Institute, NIH; Bldg. 37, Rm. 3128 Bethesda, Md. 20892. Tel:301-496-8753, Fax:301-496-8419 E-mail: Vinsonc@dc37a.nci.nih.gov. 4 Present address Laboratory of Systems Neuroscience, National Institute of Mental Health, NIH: Bldg 35 Rm 3A1014 Bethesda, MD 20892. 5 Present address Office of Provost, Massachusetts Hall, Harvard University, Cambridge, MA.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2008 November 20. Published in final edited form as:Neuroscience. (Di Chiara and Imperato, 1988;Hurd and Ungerstedt, 1989;Kalivas and Duffy, 1990;Robbins and Everitt, 1996), the downstream effects are not well understood at...

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