Abstract
Cocaine addiction is characterized by an impaired ability to develop adaptive behaviors that can compete with cocaine seeking, implying a deficit in the ability to induce plasticity in cortico-accumbens circuitry crucial for regulating motivated behavior. We found that rats withdrawn from cocaine self-administration had a marked in vivo deficit in the ability to develop long-term potentiation (LTP) and long-term depression (LTD) in the nucleus accumbens core subregion after stimulation of the prefrontal cortex. N-acetylcysteine (NAC) treatment prevents relapse in animal models and craving in humans by activating cystine-glutamate exchange and thereby stimulating extrasynaptic metabotropic glutamate receptors (mGluR). NAC treatment of rats restored the ability to induce LTP and LTD by indirectly stimulating mGluR2/3 and mGluR5, respectively. Our findings show that cocaine self-administration induces metaplasticity that inhibits further induction of synaptic plasticity, and this impairment can be reversed by NAC, a drug that also prevents relapse.
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Acknowledgements
We thank F. Thiels (University of Pittsburgh) for invaluable advice on field recording. This research was supported by US Public Health Service grants DA03906, DA12513, DA015369 and DA024355.
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K.M. was primary in conducting the study. A.P. assisted in conducting the microdialysis experiments. M.M. collected the initial preliminary data indicating that NAC would reverse the cocaine-induced loss of LTP. A.L. provided training and technical advice for the in vivo recordings. M.F.O. and J.T.G. assisted in the behavioral pharmacology experiments. K.M. and P.W.K. developed the experimental design and made the primary contributions in writing the manuscript and preparing the figures.
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Moussawi, K., Pacchioni, A., Moran, M. et al. N-Acetylcysteine reverses cocaine-induced metaplasticity. Nat Neurosci 12, 182–189 (2009). https://doi.org/10.1038/nn.2250
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DOI: https://doi.org/10.1038/nn.2250