Abstract
Increases in dopamine and glutamate transmission in the nucleus accumbens independently promote the reinstatement of cocaine seeking, an animal model of relapse. Here we have tested whether cocaine reinstatement in rats depends on interactions between accumbal dopamine and glutamate systems that are mediated by Ca2+/calmodulin-mediated kinase II (CaMKII). We show that stimulation of D1-like dopamine receptors in the nucleus accumbens shell reinstates cocaine seeking by activating L-type Ca2+ channels and CaMKII. Cocaine reinstatement is associated with D1-like dopamine receptor–dependent increases in accumbens shell CaMKII phosphorylated on Thr286 and glutamate receptor 1 (GluR1) phosphorylated on Ser831 (a known CaMKII phosphorylation site), in addition to increases in cell-surface expression of GluR1-containing AMPA receptors in the shell. Consistent with these findings, cocaine reinstatement is attenuated by intra-shell administration of AAV10-GluR1-C99, a vector that impairs the transport of GluR1-containing AMPA receptors. Thus, CaMKII may be an essential link between accumbens shell dopamine and glutamate systems involved in the neuronal plasticity underlying cocaine craving and relapse.
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Change history
01 April 2008
In the version of this article initially published, Thr286 was substituted for Ser831 in the second sentence of the concluding paragraph. The sentence should read: "The reinstatement of cocaine seeking is also associated with an increase in GluR1 phosphorylated on Ser831, a CaMKII phosphorylation site, and enhanced cell-surface expression of GluR1-containing AMPA receptors in the accumbens shell." The error has been corrected in the HTML and PDF versions of the article.
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Acknowledgements
We thank A. Pierce for administrative assistance; J. Woodward (Medical University of South Carolina) for the GluR1 cDNA; the Gene Therapy Program Vector Core (Department of Medicine, University of Pennsylvania) for the AAV2/10 rep/cap plasmid; and M. Thomas, S. Licuta, P. Kalivas and P. Vezina for discussions and specific comments on the manuscript. This research was supported by grants from the National Institutes of Health (NIH) to R.C.P. (R01 DA15214 and K02 DA18678) and E.F.T. (R21 DA18333). K.R.F. was partially supported by a National Research Service Award (NRSA) from the NIH (F30 DA19304) and an NIH training grant (T32 GM008541-7). H.D.S. was also partially supported by an NRSA from the NIH (DA16824). J.-H.J.C. and G.S.-V. received support from the Glendorn Foundation.
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All of the authors wrote and edited portions of the manuscript. S.M.A., K.R.F., G.S.-V., V.K., H.D.S. and R.C.P. performed experiments. C.E.B. and E.F.T. supplied AAV10-GluR1-C99 and provided advice on the use of this viral vector. J.-H.J.C. and G.S.-V. supervised the biochemical experiments. R.C.P. directed the behavioral experiments and analyzed all of the data.
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Anderson, S., Famous, K., Sadri-Vakili, G. et al. CaMKII: a biochemical bridge linking accumbens dopamine and glutamate systems in cocaine seeking. Nat Neurosci 11, 344–353 (2008). https://doi.org/10.1038/nn2054
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DOI: https://doi.org/10.1038/nn2054
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