Expression of the transcription factor ΔFosB in the brain controls sensitivity to cocaine

Max B. Kelz, Jingshan Chen, William A. Carlezon, Kim Whisler, Lauren Gilden, Alison M. Beckmann, Cathy Steffen, Ya-Jun Zhang, Louis Marotti, David W. Self, Tatiana Tkatch, Gytis Baranauskas, D. James Surmeier, Rachael L. Neve, Ronald S. Duman, Marina R. Picciotto and Eric J. Nestler ()
Additional contact information
Max B. Kelz: Laboratory of Molecular Psychiatry and Yale Center for Genes and Behavior, Yale University School of Medicine and Connecticut Mental Health Center
Jingshan Chen: Laboratory of Molecular Psychiatry and Yale Center for Genes and Behavior, Yale University School of Medicine and Connecticut Mental Health Center
William A. Carlezon: Laboratory of Molecular Psychiatry and Yale Center for Genes and Behavior, Yale University School of Medicine and Connecticut Mental Health Center
Kim Whisler: Laboratory of Molecular Psychiatry and Yale Center for Genes and Behavior, Yale University School of Medicine and Connecticut Mental Health Center
Lauren Gilden: Laboratory of Molecular Psychiatry and Yale Center for Genes and Behavior, Yale University School of Medicine and Connecticut Mental Health Center
Alison M. Beckmann: Laboratory of Molecular Psychiatry and Yale Center for Genes and Behavior, Yale University School of Medicine and Connecticut Mental Health Center
Cathy Steffen: Laboratory of Molecular Psychiatry and Yale Center for Genes and Behavior, Yale University School of Medicine and Connecticut Mental Health Center
Ya-Jun Zhang: Laboratory of Molecular Psychiatry and Yale Center for Genes and Behavior, Yale University School of Medicine and Connecticut Mental Health Center
Louis Marotti: Laboratory of Molecular Psychiatry and Yale Center for Genes and Behavior, Yale University School of Medicine and Connecticut Mental Health Center
David W. Self: Laboratory of Molecular Psychiatry and Yale Center for Genes and Behavior, Yale University School of Medicine and Connecticut Mental Health Center
Tatiana Tkatch: University Institute of Neuroscience, Northwestern University
Gytis Baranauskas: University Institute of Neuroscience, Northwestern University
D. James Surmeier: University Institute of Neuroscience, Northwestern University
Rachael L. Neve: Harvard Medical School, McLean Hospital, Belmont
Ronald S. Duman: Laboratory of Molecular Psychiatry and Yale Center for Genes and Behavior, Yale University School of Medicine and Connecticut Mental Health Center
Marina R. Picciotto: Laboratory of Molecular Psychiatry and Yale Center for Genes and Behavior, Yale University School of Medicine and Connecticut Mental Health Center
Eric J. Nestler: Laboratory of Molecular Psychiatry and Yale Center for Genes and Behavior, Yale University School of Medicine and Connecticut Mental Health Center

Nature, 1999, vol. 401, issue 6750, 272-276

Abstract: Abstract Acute exposure to cocaine transiently induces several Fos family transcription factors in the nucleus accumbens1, a region of the brain that is important for addiction2,3. In contrast, chronic exposure to cocaine does not induce these proteins, but instead causes the persistent expression of highly stable isoforms of ΔFosB4,5,6. ΔFosB is also induced in the nucleus accumbens by repeated exposure to other drugs of abuse, including amphetamine, morphine, nicotine and phencyclidine7,8,9,10. The sustained accumulation of ΔFosB in the nucleus accumbens indicates that this transcription factor may mediate some of the persistent neural and behavioural plasticity that accompanies chronic drug exposure1. Using transgenic mice in which ΔFosB can be induced in adults in the subset of nucleus accumbens neurons in which cocaine induces the protein, we show that ΔFosB expression increases the responsiveness of an animal to the rewarding and locomotor-activating effects of cocaine. These effects of ΔFosB appear to be mediated partly by induction of the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole) glutamate receptor subunit GluR2 in the nucleus accumbens. These results support a model in which ΔFosB, by altering gene expression, enhances sensitivity to cocaine and may thereby contribute to cocaine addiction.

Date: 1999
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DOI: 10.1038/45790

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