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Cocaine-evoked synaptic plasticity: persistence in the VTA triggers adaptations in the NAc

Abstract

Addictive drugs hijack mechanisms of learning and memory that normally underlie reinforcement of natural rewards and induce synaptic plasticity of glutamatergic transmission in the mesolimbic dopamine (DA) system. In the ventral tegmental area (VTA), a single exposure to cocaine efficiently triggers NMDA receptor–dependent synaptic plasticity in DA neurons, whereas plasticity in the nucleus accumbens (NAc) occurs only after repeated injections. Whether these two forms of plasticity are independent or hierarchically organized remains unknown. We combined ex vivo electrophysiology in acute brain slices with behavioral assays modeling drug relapse in mice and found that the duration of the cocaine-evoked synaptic plasticity in the VTA is gated by mGluR1. Overriding mGluR1 in vivo made the potentiation in the VTA persistent. This led to synaptic plasticity in the NAc, which contributes to cocaine-seeking behavior after protracted withdrawal. Impaired mGluR1 function in vulnerable individuals could represent a first step in the recruitment of the neuronal network that underlies drug addiction.

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Figure 1: Disruption of Homer 1b/c–mGluR interaction in the VTA renders cocaine-evoked plasticity persistent.
Figure 2: Bi-directional modulation of mGluR1 controls the persistency of cocaine-evoked plasticity in VTA.
Figure 3: Modulation of mGluR1 controls cocaine-evoked plasticity in the NAc.
Figure 4: Early and enduring synaptic plasticity in the NAc after a single injection of cocaine.
Figure 5: Disruption of NMDARs in midbrain DA neurons abolishes enduring plasticity in the NAc and reduces incubation of craving.

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Acknowledgements

We thank members of the Lüscher laboratory, as well as B.J. Everitt, M. Frerking, A. Lüthi, M. Serafin, M. Carta and C.F. Valenzuela for helpful discussions and suggestions regarding the manuscript. R. Sprengel (Max Planck Institute Heidelberg) generated the NR12loxP/loxP mouse line and G. Schütz (Deutsches Krebsforschungszentrum Heidelberg) provided the NR1DAT-CreERT2 mouse line. C.L. is supported by grants from the Swiss National Science Foundation and the Swiss initiative in system biology (SystemsX: neurochoice). R.S. is supported by Nationales Genomforschungsnetz and Deutsche Forschungsgemeinschaft.

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M.M. carried out the electrophysiology experiments. B.H. performed the behavioral experiments. D.E. generated the mutant mice. J.R.P. bred the mice for the behavioral experiments and injected them with tamoxifen. C.L. designed the study with M.M. and C.C. and wrote the manuscript with the help of M.M. and R.S.

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Correspondence to Christian Lüscher.

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Mameli, M., Halbout, B., Creton, C. et al. Cocaine-evoked synaptic plasticity: persistence in the VTA triggers adaptations in the NAc. Nat Neurosci 12, 1036–1041 (2009). https://doi.org/10.1038/nn.2367

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