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


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.

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Figure 1: ΔFosB expression in NAc of bitransgenic NSE-tTA × TetOp–ΔfosB (N+Δ+) mice.
Figure 2: Effect of ΔFosB expression on locomotor activity.
Figure 3: Effect of ΔFosB expression on place conditioning.
Figure 4: Effect of ΔFosB expression on levels of glutamate receptor subunits and AP-1 binding in NAc.
Figure 5: Effect of HSV vectors in NAc on place conditioning to cocaine.


  1. 1

    Nestler,E. J. & Aghajanian,G. K. Molecular and cellular basis of addiction. Science 278, 58–63 (1997).

  2. 2

    Koob,G. F. & Le Moal,M. Drug abuse: hedonic homeostatic dysregulation. Science 278, 52–58 (1997).

  3. 3

    Wise,R. A. Drug-activation of brain reward pathways. Drug Alcohol Depend. 51, 13–22 (1998).

  4. 4

    Hope,B. T. et al. Induction of a long-lasting AP-1 complex composed of altered Fos-like proteins in brain by chronic cocaine and other chronic treatments. Neuron 13, 1235–1244 (1994).

  5. 5

    Hiroi,N. et al. FosB mutant mice: loss of chronic cocaine induction of Fos-related proteins and heightened sensitivity to cocaine's psychomotor and rewarding effects. Proc. Natl Acad. Sci. USA 94, 10397–10402 (1997).

  6. 6

    Chen,J., Kelz,M. B., Hope,B. T., Nakabeppu,Y. & Nestler,E. J. Chronic Fos-related antigens: stable variants of deltaFosB induced in brain by chronic treatments. J. Neurosci. 17, 4933–4941 (1997).

  7. 7

    Nye,H. E., Hope,B. T., Kelz,M. B., Iadarola,M. & Nestler, E J. Pharmacological studies of the regulation of chronic Fos-related antigen induction by cocaine in the striatum and nucleus accumbens. J. Pharmacol. Exp. Ther. 275, 1671–1680 (1995).

  8. 8

    Nye,H. E. & Nestler,E. J. Induction of chronic Fos-related antigens in rat brain by chronic morphine administration. Mol. Pharmacol. 49, 636–645 (1996).

  9. 9

    Pich,E. M. et al. Common neural substrates for the addictive properties of nicotine and cocaine. Science 275, 83–86 (1997).

  10. 10

    Atkins,J., Carlezon,W. A., Chlan,J., Nye,H. E. & Nestler,E. J. Region-specific induction of ΔFosB by repeated administration of typical versus atypical antipsychotic drugs. Synapse 33, 118–128 (1999).

  11. 11

    Furth,P. A. et al. Temporal control of gene expression in transgenic mice by a tetracycline-responsive promoter. Proc. Natl Acad. Sci. USA 91, 9302–9306 (1994).

  12. 12

    Chen,J. et al. Transgenic animals with inducible, targeted gene expression in brain. Mol. Pharmacol. 54, 495–503 (1998).

  13. 13

    Moratalla,R., Vallejo,M., Elibol,B. & Graybiel,A. M. D1-class dopamine receptors influence cocaine-induced persistent expression of Fos-related proteins in striatum. Neuroreport 8, 1–5 (1996).

  14. 14

    Wolf,M. E. The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants. Prog. Neurobiol. 54, 679–720 (1998).

  15. 15

    Robinson, T E. & Berridge,K. C. The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res. Rev. 18, 247–291 (1993).

  16. 16

    Kalivas,P. W., Pierce,R. C., Cornish,J. & Sorg,B. A. A role for sensitization in craving and relapse in cocaine addiction. J. Psychopharmacol. 12, 49–53 (1998).

  17. 17

    Carlezon, W. A. Jr et al. Regulation of cocaine reward by CREB. Science 282, 2272–2275 (1998).

  18. 18

    Pennartz,C. M., Groenewege,H. J. & Lopes da Silva,F. H. The nucleus accumbens as a complex of functionally distinct neuronal ensembles: an integration of behavioural, electrophysiological and anatomical data. Prog. Neurobiol. 42, 719–761 (1994).

  19. 19

    White,F. J., Hu,X. T. & Zhang,X. F. Neuroadaptations in nucleus accumbens neurons resulting from repeated cocaine administration. Adv. Pharmacol. 42, 1006–1009 (1998).

  20. 20

    Bai,G. & Kusiak,J. W. Cloning and analysis of the 5′ flanking sequence of the rat N-methyl-D-aspartate receptor 1 (NMDAR1) gene. Biochim. Biophys. Acta 1152, 197–200 (1993).

  21. 21

    Hiroi,N. et al. Essential role of the fosB gene in molecular, cellular, and behavioral actions of electroconvulsive seizures. J. Neurosci. 18, 6952–6962 (1998).

  22. 22

    Myers,S. J., Dingledine,R. & Borges,K. Genetic regulation of glutamate receptor ion channels. Annu. Rev. Pharmacol. Toxicol. 39, 221–241 (1999).

  23. 23

    Brene,S., Messer,C., Okado,H., Heinemann,S. F. & Nestler,E. J. Regulation of AMPA receptor promotor activity by neurotrophic factors. Soc. Neurosci. Abs. 23, 923 (1997).

  24. 24

    Hollmann,M. & Heinemann,S. Cloned glutamate receptors. Annu. Rev. Neurosci. 17, 31–108 (1994).

  25. 25

    Seeburg,P. H., Higuchi,M. & Sprengel,R. RNA editing of brain glutamate receptor channels: mechanism and physiology. Brain Res. Rev. 26, 217–229 (1998).

  26. 26

    Carlezon, W. A. Jr et al. Sensitization to morphine induced by viral-mediated gene transfer. Science 277, 812–814 (1997).

  27. 27

    Rocha,B. A. et al. Increased vulnerability to cocaine in mice lacking the serotonin-1B receptor. Nature 393, 175–178 (1998).

  28. 28

    Peoples,L. L., Uzwiak,A. J., Guyette,F. X. & West,M. O. Tonic inhibition of single nucleus accumbens neurons in the rat: a predominant but not exclusive firing pattern induced by cocaine self-administration sessions. Neuroscience 86, 13–22 (1998).

  29. 29

    Surmeier,D. J., Song,W. J. & Yan,Z. Coordinated expression of dopamine receptors in neostriatal medium spiny neurons. J. Neurosci. 16, 6579–6591 (1996).

  30. 30

    Gerfen,C. R., McGinty,J. F. & Young,W. S. Dopamine differentially regulates dynorphin, substance P, and enkephalin expression in striatal neurons: in situ hybridization histochemical analysis. J. Neurosci. 11, 1016–1031 (1991).

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We thank H. Nadim and P. Jatlow for performing serum cocaine measurements; A. Withers-Lowin for assistance with the Morris water maze; and A. Sangoram, N. Hiroi, A. Eisch, D. Russell, S. Numan and D. Wolf for helpful comments. This work was supported by grants (to E.J.N.) and a predoctoral NRSA fellowship (to M.B.K.) from the National Institute on Drug Abuse, and by the Abraham Ribicoff Research Facilities of the Connecticut Mental Health Center.

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Correspondence to Eric J. Nestler.

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Kelz, M., Chen, J., Carlezon, W. et al. Expression of the transcription factor ΔFosB in the brain controls sensitivity to cocaine. Nature 401, 272–276 (1999).

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