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


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.


  1. Kalivas, P.W. Glutamate systems in cocaine addiction. Curr. Opin. Pharmacol. 4, 23–29 (2004).

    Article  CAS  Google Scholar 

  2. Kauer, J.A. & Malenka, R.C. Synaptic plasticity and addiction. Nat. Rev. Neurosci. 8, 844–858 (2007).

    Article  CAS  Google Scholar 

  3. Thomas, M.J., Kalivas, P.W. & Shaham, Y. Neuroplasticity in the mesolimbic dopamine system and cocaine addiction. Br. J. Pharmacol. 154, 327–342 (2008).

    Article  CAS  Google Scholar 

  4. Ungless, M.A., Whistler, J.L., Malenka, R.C. & Bonci, A. Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons. Nature 411, 583–587 (2001).

    Article  CAS  Google Scholar 

  5. 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).

    Article  CAS  Google Scholar 

  6. Argilli, E., Sibley, D.R., Malenka, R.C., England, P.M. & Bonci, A. Mechanism and time course of cocaine-induced long-term potentiation in the ventral tegmental area. J. Neurosci. 28, 9092–9100 (2008).

    Article  CAS  Google Scholar 

  7. Saal, D., Dong, Y., Bonci, A. & Malenka, R.C. Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons. Neuron 37, 577–582 (2003).

    Article  CAS  Google Scholar 

  8. Borgland, S.L., Malenka, R.C. & Bonci, A. Acute and chronic cocaine-induced potentiation of synaptic strength in the ventral tegmental area: electrophysiological and behavioral correlates in individual rats. J. Neurosci. 24, 7482–7490 (2004).

    Article  CAS  Google Scholar 

  9. Chen, B.T. et al. Cocaine but not natural reward self-administration nor passive cocaine infusion produces persistent LTP in the VTA. Neuron 59, 288–297 (2008).

    Article  CAS  Google Scholar 

  10. Kourrich, S., Rothwell, P.E., Klug, J.R. & Thomas, M.J. Cocaine experience controls bidirectional synaptic plasticity in the nucleus accumbens. J. Neurosci. 27, 7921–7928 (2007).

    Article  CAS  Google Scholar 

  11. Conrad, K.L. et al. Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving. Nature 454, 118–121 (2008).

    Article  CAS  Google Scholar 

  12. Churchill, L., Swanson, C.J., Urbina, M. & Kalivas, P.W. Repeated cocaine alters glutamate receptor subunit levels in the nucleus accumbens and ventral tegmental area of rats that develop behavioral sensitization. J. Neurochem. 72, 2397–2403 (1999).

    Article  CAS  Google Scholar 

  13. Boudreau, A.C. & Wolf, M.E. Behavioral sensitization to cocaine is associated with increased AMPA receptor surface expression in the nucleus accumbens. J. Neurosci. 25, 9144–9151 (2005).

    Article  CAS  Google Scholar 

  14. Grimm, J.W., Hope, B.T., Wise, R.A. & Shaham, Y. Neuroadaptation. Incubation of cocaine craving after withdrawal. Nature 412, 141–142 (2001).

    Article  CAS  Google Scholar 

  15. Ping, A., Xi, J., Prasad, B.M., Wang, M.H. & Kruzich, P.J. Contributions of nucleus accumbens core and shell GluR1 containing AMPA receptors in AMPA- and cocaine-primed reinstatement of cocaine-seeking behavior. Brain Res. 1215, 173–182 (2008).

    Article  CAS  Google Scholar 

  16. Kessels, H.W. & Malinow, R. Synaptic AMPA receptor plasticity and behavior. Neuron 61, 340–350 (2009).

    Article  CAS  Google Scholar 

  17. Mameli, M., Balland, B., Lujan, R. & Lüscher, C. Rapid synthesis and synaptic insertion of GluR2 for mGluR-LTD in the ventral tegmental area. Science 317, 530–533 (2007).

    Article  CAS  Google Scholar 

  18. Mao, L. et al. The scaffold protein Homer1b/c links metabotropic glutamate receptor 5 to extracellular signal–regulated protein kinase cascades in neurons. J. Neurosci. 25, 2741–2752 (2005).

    Article  CAS  Google Scholar 

  19. Ronesi, J.A. & Huber, K.M. Homer interactions are necessary for metabotropic glutamate receptor–induced long-term depression and translational activation. J. Neurosci. 28, 543–547 (2008).

    Article  CAS  Google Scholar 

  20. Moroni, F. et al. Pharmacological characterization of 1-aminoindan-1,5-dicarboxylic acid, a potent mGluR1 antagonist. J. Pharmacol. Exp. Ther. 281, 721–729 (1997).

    CAS  PubMed  Google Scholar 

  21. Thomas, M.J., Beurrier, C., Bonci, A. & Malenka, R.C. Long-term depression in the nucleus accumbens: a neural correlate of behavioral sensitization to cocaine. Nat. Neurosci. 4, 1217–1223 (2001).

    Article  CAS  Google Scholar 

  22. Engblom, D. et al. Glutamate receptors on dopamine neurons control the persistence of cocaine seeking. Neuron 59, 497–508 (2008).

    Article  CAS  Google Scholar 

  23. Anderson, S.M. et al. CaMKII: a biochemical bridge linking accumbens dopamine and glutamate systems in cocaine seeking. Nat. Neurosci. 11, 344–353 (2008).

    Article  CAS  Google Scholar 

  24. Haber, S.N., Fudge, J.L. & McFarland, N.R. Striatonigrostriatal pathways in primates form an ascending spiral from the shell to the dorsolateral striatum. J. Neurosci. 20, 2369–2382 (2000).

    Article  CAS  Google Scholar 

  25. Ikemoto, S. Dopamine reward circuitry: two projection systems from the ventral midbrain to the nucleus accumbens-olfactory tubercle complex. Brain Res. Rev. 56, 27–78 (2007).

    Article  CAS  Google Scholar 

  26. Everitt, B.J. & Robbins, T.W. Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nat. Neurosci. 8, 1481–1489 (2005).

    Article  CAS  Google Scholar 

  27. Lüscher, C. & Bellone, C. Cocaine-evoked synaptic plasticity: a key to addiction? Nat. Neurosci. 11, 737–738 (2008).

    Article  Google Scholar 

  28. Zweifel, L.S., Argilli, E., Bonci, A. & Plamiter, R.D. Role of NMDA receptors in dopamine neurons for plasticity and addictive behaviors. Neuron 59, 486–496 (2008).

    Article  CAS  Google Scholar 

  29. Vezina, P. & Queen, A.L. Induction of locomotor sensitization by amphetamine requires the activation of NMDA receptors in the rat ventral tegmental area. Psychopharmacology (Berl.) 151, 184–191 (2000).

    Article  CAS  Google Scholar 

  30. Harris, G.C., Wimmer, M., Byrne, R. & Aston-Jones, G. Glutamate-associated plasticity in the ventral tegmental area is necessary for conditioning environmental stimuli with morphine. Neuroscience 129, 841–847 (2004).

    Article  CAS  Google Scholar 

  31. Dong, Y. et al. Cocaine-induced potentiation of synaptic strength in dopamine neurons: behavioral correlates in GluRA−/− mice. Proc. Natl. Acad. Sci. USA 101, 14282–14287 (2004).

    Article  CAS  Google Scholar 

  32. Mead, A.N., Brown, G., Le Merrer, J. & Stephens, D.N. Effects of deletion of gria1 or gria2 genes encoding glutamatergic AMPA-receptor subunits on place preference conditioning in mice. Psychopharmacology (Berl.) 179, 164–171 (2005).

    Article  CAS  Google Scholar 

  33. Carlezon, W.A. Jr & Nestler, E.J. Elevated levels of GluR1 in the midbrain: a trigger for sensitization to drugs of abuse? Trends Neurosci. 25, 610–615 (2002).

    Article  CAS  Google Scholar 

  34. Lammel, S. et al. Unique properties of mesoprefrontal neurons within a dual mesocorticolimbic dopamine system. Neuron 57, 760–773 (2008).

    Article  CAS  Google Scholar 

  35. Zhao, S. et al. Generation of embryonic stem cells and transgenic mice expressing green fluorescence protein in midbrain dopaminergic neurons. Eur. J. Neurosci. 19, 1133–1140 (2004).

    Article  Google Scholar 

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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).

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