Abstract
Drugs of abuse induce long-lasting changes in neural circuits that may underlie core components of addiction. Here we focus on glutamatergic synapses onto dopamine (DA) neurons of the ventral tegmental area (VTA). Using an 'ex vivo' approach in mice, we show that a single injection of cocaine caused strong rectification and conferred sensitivity to the polyamine Joro spider toxin (JST) of AMPAR-mediated excitatory postsynaptic currents (AMPAR EPSCs), indicating the recruitment of receptors that lack GluR2. This qualitative change in transmission was paralleled by an increase in the AMPAR:NMDAR ratio and was prevented by interfering with the protein interacting with C kinase-1 (PICK1) in vivo. Activation of metabotropic glutamate receptors (mGluR1s) by intraperitoneal injection of a positive modulator depotentiated synapses and abolished rectification in slices of cocaine-treated mice, revealing a mechanism to reverse cocaine-induced synaptic plasticity in vivo.
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Acknowledgements
We thank the members of the Lüscher lab for helpful discussions; M. Frerking, R.C. Malenka, R.A. Nicoll and M. Serafin for comments on an earlier version of the manuscript; and F. Loctin for technical support. C.L. is supported by the Swiss National Science Foundation, the Leenaards Foundation, the Human Frontier Science Program and a grant from the European community (SYNSCAFF).
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Supplementary Fig. 1
Representative examples of AMPAR-EPSCs recorded in drug-naïve rat and mouse. (PDF 797 kb)
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Bellone, C., Lüscher, C. Cocaine triggered AMPA receptor redistribution is reversed in vivo by mGluR-dependent long-term depression. Nat Neurosci 9, 636–641 (2006). https://doi.org/10.1038/nn1682
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DOI: https://doi.org/10.1038/nn1682
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