Elsevier

Neuroscience

Volume 152, Issue 4, 9 April 2008, Pages 1040-1053
Neuroscience

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

https://doi.org/10.1016/j.neuroscience.2008.01.045Get rights and content

Abstract

We have expressed A-FOS, an inhibitor of activator protein-1 (AP-1) DNA binding, in adult mouse striatal neurons. We observed 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 response to cocaine. We analyzed mRNA from the striatum before and 4 and 24 h 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 h following cocaine treatment relative to controls. However, 24 h after an acute cocaine treatment, 84 genes were identified that were differentially expressed between the A-FOS and control mice. Fifty-six genes are down-regulated while 28 genes are up-regulated including previously identified candidates for addiction including brain-derived neurotrophic factor and period homolog 1. 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 with human genome scans of addiction to identify potential genes in humans that are involved in addiction.

Section snippets

Generation and initial characterization of mice

All animal procedures were performed according to NIH guidelines on the ethical use of animals. Every effort was made to minimize the number of animals used and their suffering. Animals were housed three to five per cage on a 12-h light/dark cycle with free access to food and water. The TetOp-A-FOS mice have been previously described (Gerdes et al., 2006). These mice were produced and maintained on a FVB/N background. To produce A-FOS expression in the brain the TetOp-A-FOS line was crossed

Expression of A-FOS in the brain

To express A-FOS in the striatum we used the two-transgene tetracycline transactivator system. The TetOp-A-FOS line (Gerdes et al., 2006) that expresses A-FOS using the Tet-O promoter was crossed with a line using the NSE promoter to drive expression of tTA (NSE-tTA Line A) (Chen et al., 1998). Coronal brain sections were analyzed by in situ hybridization to confirmed the A-FOS mRNA expression patterns (Fig. 1). A-FOS expression was strong and homogenous throughout the striatum including the

Discussion

We expressed in the adult striatum A-FOS a novel AP-1 dominant negative. Expression does not affect baseline behavior or the initial behavioral response to cocaine. However, following repeated cocaine treatments, A-FOS animals displayed enhanced cocaine-induced hyperlocomotion compared with littermates. A-FOS had a similar affect on striatal gene expression, therefore no changes at baseline or 4 h following a single injection of cocaine, but producing significant effects on gene expression at

Acknowledgments

We would like to thank Eric Nestler for providing the NSE-tTA mice used in these experiments, and Shari Thomas for her technical support. We would also like to thank Mike Iadarola for his helpful comments on the manuscript. R.F.P. would also like to thank Alexei Morozov (Unit of Behavioral Genetics, National Institute of Mental Health, NIH) and Charles Gerfen (Laboratory of Systems Neuroscience, National Institute of Mental Health, NIH) for providing support for these studies.

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    Present address: Laboratory of Systems Neuroscience, National Institute of Mental Health, NIH, Building 35, Room 3A1014, Bethesda, MD 20892, USA (R. F. Paletzki); Office of Provost, Massachusetts Hall, Harvard University, Cambridge, MA, USA (S. E. Hyman).

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