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PNAS 98 (20): 11042-11046

Copyright © 2001 by the National Academy of Sciences.

Colloquium Paper

COLLOQUIUM PAPER

{Delta}FosB: A sustained molecular switch for addiction

Eric J. Nestler*, Michel Barrot, and David W. Self

Department of Psychiatry and Center for Basic Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9070

Abstract: The longevity of some of the behavioral abnormalities that characterize drug addiction has suggested that regulation of neural gene expression may be involved in the process by which drugs of abuse cause a state of addiction. Increasing evidence suggests that the transcription factor {Delta}FosB represents one mechanism by which drugs of abuse produce relatively stable changes in the brain that contribute to the addiction phenotype. {Delta}FosB, a member of the Fos family of transcription factors, accumulates within a subset of neurons of the nucleus accumbens and dorsal striatum (brain regions important for addiction) after repeated administration of many kinds of drugs of abuse. Similar accumulation of {Delta}FosB occurs after compulsive running, which suggests that {Delta}FosB may accumulate in response to many types of compulsive behaviors. Importantly, {Delta}FosB persists in neurons for relatively long periods of time because of its extraordinary stability. Therefore, {Delta}FosB represents a molecular mechanism that could initiate and then sustain changes in gene expression that persist long after drug exposure ceases. Studies in inducible transgenic mice that overexpress either {Delta}FosB or a dominant negative inhibitor of the protein provide direct evidence that {Delta}FosB causes increased sensitivity to the behavioral effects of drugs of abuse and, possibly, increased drug seeking behavior. This work supports the view that {Delta}FosB functions as a type of sustained "molecular switch" that gradually converts acute drug responses into relatively stable adaptations that contribute to the long-term neural and behavioral plasticity that underlies addiction.

* To whom reprint requests should be addressed. E-mail: eric.nestler{at}utsouthwestern.edu.

This paper was presented at the Inaugural Arthur M. Sackler Colloquium of the National Academy of Sciences, "Neural Signaling," held February 15–17, 2001, at the National Academy of Sciences in Washington, DC.

{dagger} Werme, M., Nestler, E. J. & Brene, S. (2001) Soc. Neurosci. Abstr., in press.

{ddagger} Whisler, K., Kelz, M. B., Chen, J. S., Nestler, E. J. & Self, D. W. (1999) Soc. Neurosci. Abstr. 25, 811.

Peakman, M.-C., Colby, C., Duman, R. S., Allen, M. R., Stock, J. L., NcNeish, J. D., Kelz, M. B., Chen, J. S., Nestler, E. J. & Schaeffer, E. (2000) Soc. Neurosci. Abstr. 26, 124.

|| Shaw, T. Z., Gilden, L., Kelz, M., Chen, J. & Nestler, E. J. (2000) Soc. Neurosci. Abstr. 26, 525.

§ Roberts, A., Picetti, R., Nestler, E. J., Koob, G. F. (2001) Soc. Neurosci. Abstr., in press.

** Barrot, M., Olivier, J. D. A., Zachariou, V., Neve, R. L. & Nestler, E. J. (2000) Soc. Neurosci. Abstr. 26, 485.

{ddagger}{ddagger} Norrholm, S. D., Bibb, J. A., Nestler, E. J., Ouimet, C. C., Taylor, J. R. & Greengard, P. (2001) Soc. Neurosci. Abstr., in press.

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