Abstract

Repeated cocaine administration increases the dendritic arborization of nucleus accumbens neurons, but the underlying signaling events remain unknown. Here we show that repeated exposure to cocaine negatively regulates the active form of Rac1, a small GTPase that controls actin remodeling in other systems. Further, we show, using viral-mediated gene transfer, that overexpression of a dominant negative mutant of Rac1 or local knockout of Rac1 is sufficient to increase the density of immature dendritic spines on nucleus accumbens neurons, whereas overexpression of a constitutively active Rac1 or light activation of a photoactivatable form of Rac1 blocks the ability of repeated cocaine exposure to produce this effect. Downregulation of Rac1 activity likewise promotes behavioral responses to cocaine exposure, with activation of Rac1 producing the opposite effect. These findings establish that Rac1 signaling mediates structural and behavioral plasticity in response to cocaine exposure.

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Acknowledgements

We thank S. Golden, A. Robison and V. Vialou for helpful discussions and comments on the manuscript. This work was supported by grants from the US National Institute on Drug Abuse (R01 DA14133, P01 DA08227) and US National Institute of Mental Health (R01 MH51399).

Author information

Affiliations

  1. Fishberg Department of Neuroscience and Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York, USA.

    • David M Dietz
    • , Haosheng Sun
    • , Mary Kay Lobo
    • , Michael E Cahill
    • , Benjamin Chadwick
    • , Virginia Gao
    • , Ja Wook Koo
    • , Michelle S Mazei-Robison
    • , Caroline Dias
    • , Ian Maze
    • , Diane Damez-Werno
    • , Karen C Dietz
    • , Kimberly N Scobie
    • , Deveroux Ferguson
    • , Daniel Christoffel
    • , Yoko Ohnishi
    • , Georgia E Hodes
    • , Scott J Russo
    •  & Eric J Nestler
  2. Division of Experimental Hematology and Cancer Biology, Children's Hospital Research Foundation, University of Cincinnati, Cincinnati, Ohio, USA.

    • Yi Zheng
  3. Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Rachael L Neve
  4. Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Klaus M Hahn

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Contributions

D.M.D., S.J.R. and E.J.N. were responsible for overall study design. D.M.D., H.S., K.C.D., C.D. and I.M. designed and conducted GTPase activity assays and analyzed the data. D.M.D., M.E.C., J.W.K. and D.F. carried out the stereotaxic surgeries and behavioral experiments. D.M.D., M.S.M.-R., D.D.-W., V.G. and H.S. carried out and analyzed the western blots. D.M.D., D.C. and V.G. scanned, counted and analyzed the spine data. D.M.D., M.K.L., H.S., K.N.S., G.E.H., S.J.R., Y.O. and K.M.H. designed and did the necessary cloning and conducted the optical Rac1-pa experiments. Y.Z. provided the floxed Rac1 mice and expertise in Rac1 signaling; R.L.N. constructed and provided the viral vectors for gene transfer. D.M.D. and E.J.N. wrote the paper with the help of the other authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Eric J Nestler.

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https://doi.org/10.1038/nn.3094

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