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

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.

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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.

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Acknowledgements

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). https://doi.org/10.1038/45790

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