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Reversal of cocaine-evoked synaptic potentiation resets drug-induced adaptive behaviour

Abstract

Drug-evoked synaptic plasticity is observed at many synapses and may underlie behavioural adaptations in addiction1. Mechanistic investigations start with the identification of the molecular drug targets. Cocaine, for example, exerts its reinforcing2 and early neuroadaptive effects3 by inhibiting the dopamine transporter, thus causing a strong increase in mesolimbic dopamine. Among the many signalling pathways subsequently engaged, phosphorylation of the extracellular signal-regulated kinase (ERK) in the nucleus accumbens4 is of particular interest because it has been implicated in NMDA-receptor and type 1 dopamine (D1)-receptor-dependent synaptic potentiation5 as well as in several behavioural adaptations6,7,8. A causal link between drug-evoked plasticity at identified synapses and behavioural adaptations, however, is missing, and the benefits of restoring baseline transmission have yet to be demonstrated. Here we find that cocaine potentiates excitatory transmission in D1-receptor-expressing medium-sized spiny neurons (D1R-MSNs) in mice via ERK signalling with a time course that parallels locomotor sensitization. Depotentiation of cortical nucleus accumbens inputs by optogenetic stimulation in vivo efficiently restored normal transmission and abolished cocaine-induced locomotor sensitization. These findings establish synaptic potentiation selectively in D1R-MSNs as a mechanism underlying a core component of addiction, probably by creating an imbalance between distinct populations of MSNs in the nucleus accumbens. Our data also provide proof of principle that reversal of cocaine-evoked synaptic plasticity can treat behavioural alterations caused by addictive drugs and may inspire novel therapeutic approaches involving deep brain stimulation or transcranial magnetic stimulation.

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Figure 1: Cocaine disrupts HFS-induced LTP in D1R-MSNs of the nucleus accumbens by potentiation of excitatory afferents.
Figure 2: HFS LTP and cocaine-evoked potentiation both depend on ERK activation.
Figure 3: Reversal of cocaine-evoked potentiation abolishes locomotor sensitization to cocaine.
Figure 4: Optogenetic depotentiation resets behavioural sensitization induced by chronic cocaine injections.

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References

  1. Lüscher, C. & Malenka, R. C. Drug-evoked synaptic plasticity in addiction: from molecular changes to circuit remodeling. Neuron 69, 650–663 (2011)

    Article  Google Scholar 

  2. Chen, R. et al. Abolished cocaine reward in mice with a cocaine-insensitive dopamine transporter. Proc. Natl Acad. Sci. USA 103, 9333–9338 (2006)

    Article  ADS  CAS  Google Scholar 

  3. Brown, M. T. et al. Drug-driven AMPA receptor redistribution mimicked by selective dopamine neuron stimulation. PLoS ONE 5, e15870 (2010)

    Article  ADS  CAS  Google Scholar 

  4. Valjent, E., Pages, C., Herve, D., Girault, J. A. & Caboche, J. Addictive and non-addictive drugs induce distinct and specific patterns of ERK activation in mouse brain. Eur. J. Neurosci. 19, 1826–1836 (2004)

    Article  Google Scholar 

  5. Pascoli, V. et al. Cyclic adenosine monophosphate-independent tyrosine phosphorylation of NR2B mediates cocaine-induced extracellular signal-regulated kinase activation. Biol. Psychiatry 69, 218–227 (2011)

    Article  CAS  Google Scholar 

  6. Lu, L., Koya, E., Zhai, H., Hope, B. T. & Shaham, Y. Role of ERK in cocaine addiction. Trends Neurosci. 29, 695–703 (2006)

    Article  CAS  Google Scholar 

  7. Girault, J. A., Valjent, E., Caboche, J. & Herve, D. ERK2: a logical AND gate critical for drug-induced plasticity? Curr. Opin. Pharmacol. 7, 77–85 (2007)

    Article  CAS  Google Scholar 

  8. 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 

  9. Bertran-Gonzalez, J. et al. Opposing patterns of signaling activation in dopamine D1 and D2 receptor-expressing striatal neurons in response to cocaine and haloperidol. J. Neurosci. 28, 5671–5685 (2008)

    Article  CAS  Google Scholar 

  10. Kramer, P. F. et al. Dopamine D2 receptor overexpression alters behavior and physiology in Drd2-EGFP mice. J. Neurosci. 31, 126–132 (2011)

    Article  CAS  Google Scholar 

  11. Lammel, S., Ion, D. I., Roeper, J. & Malenka, R. C. Projection-specific modulation of dopamine neuron synapses by aversive and rewarding stimuli. Neuron 70, 855–862 (2011)

    Article  CAS  Google Scholar 

  12. Wolf, M. E. The Bermuda Triangle of cocaine-induced neuroadaptations. Trends Neurosci. 33, 391–398 (2010)

    Article  CAS  Google Scholar 

  13. 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 

  14. 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 

  15. Boudreau, A. C., Reimers, J. M., Milovanovic, M. & Wolf, M. E. Cell surface AMPA receptors in the rat nucleus accumbens increase during cocaine withdrawal but internalize after cocaine challenge in association with altered activation of mitogen-activated protein kinases. J. Neurosci. 27, 10621–10635 (2007)

    Article  CAS  Google Scholar 

  16. English, J. D. & Sweatt, J. D. A requirement for the mitogen-activated protein kinase cascade in hippocampal long term potentiation. J. Biol. Chem. 272, 19103–19106 (1997)

    Article  CAS  Google Scholar 

  17. Xie, G. Q. et al. Ethanol attenuates the HFS-induced, ERK-mediated LTP in a dose-dependent manner in rat striatum. Alcohol. Clin. Exp. Res. 33, 121–128 (2009)

    Article  CAS  Google Scholar 

  18. Shen, W., Flajolet, M., Greengard, P. & Surmeier, D. J. Dichotomous dopaminergic control of striatal synaptic plasticity. Science 321, 848–851 (2008)

    Article  ADS  CAS  Google Scholar 

  19. Zhu, J. J., Qin, Y., Zhao, M., Van Aelst, L. & Malinow, R. Ras and Rap control AMPA receptor trafficking during synaptic plasticity. Cell 110, 443–455 (2002)

    Article  CAS  Google Scholar 

  20. Valjent, E. et al. Regulation of a protein phosphatase cascade allows convergent dopamine and glutamate signals to activate ERK in the striatum. Proc. Natl Acad. Sci. USA 102, 491–496 (2005)

    Article  ADS  CAS  Google Scholar 

  21. Pierce, R. C., Pierce-Bancroft, A. F. & Prasad, B. M. Neurotrophin-3 contributes to the initiation of behavioral sensitization to cocaine by activating the Ras/mitogen-activated protein kinase signal transduction cascade. J. Neurosci. 19, 8685–8695 (1999)

    Article  CAS  Google Scholar 

  22. Valjent, E. et al. Mechanisms of locomotor sensitization to drugs of abuse in a two-injection protocol. Neuropsychopharmacology 35, 401–415 (2010)

    Article  CAS  Google Scholar 

  23. Brami-Cherrier, K., Roze, E., Girault, J. A., Betuing, S. & Caboche, J. Role of the ERK/MSK1 signalling pathway in chromatin remodelling and brain responses to drugs of abuse. J. Neurochem. 108, 1323–1335 (2009)

    Article  CAS  Google Scholar 

  24. Sesack, S. R., Deutch, A. Y., Roth, R. H. & Bunney, B. S. Topographical organization of the efferent projections of the medial prefrontal cortex in the rat: an anterograde tract-tracing study with Phaseolus vulgaris leucoagglutinin. J. Comp. Neurol. 290, 213–242 (1989)

    Article  CAS  Google Scholar 

  25. LaLumiere, R. T., Niehoff, K. E. & Kalivas, P. W. The infralimbic cortex regulates the consolidation of extinction after cocaine self-administration. Learn. Mem. 17, 168–175 (2010)

    Article  CAS  Google Scholar 

  26. Lobo, M. K. et al. Cell type-specific loss of BDNF signaling mimics optogenetic control of cocaine reward. Science 330, 385–390 (2010)

    Article  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  29. Robinson, T. E. & Kolb, B. Structural plasticity associated with exposure to drugs of abuse. Neuropharmacology 47 (suppl. 1). 33–46 (2004)

    Article  CAS  Google Scholar 

  30. Vanderschuren, L. J. & Pierce, R. C. Sensitization processes in drug addiction. Curr. Top. Behav. Neurosci. 3, 179–195 (2010)

    Article  Google Scholar 

  31. Mameli, M. et al. Cocaine-evoked synaptic plasticity: persistence in the VTA triggers adaptations in the nucleus accumbens. Nature Neurosci. 12, 1036–1041 (2009)

    Article  CAS  Google Scholar 

  32. Gong, S. et al. Targeting Cre recombinase to specific neuron populations with bacterial artificial chromosome constructs. J. Neurosci. 27, 9817–9823 (2007)

    Article  CAS  Google Scholar 

  33. Kombian, S. B. & Malenka, R. C. Simultaneous LTP of non-NMDA- and LTD of NMDA-receptor-mediated responses in the nucleus accumbens. Nature 368, 242–246 (1994)

    Article  ADS  CAS  Google Scholar 

  34. Pennartz, C. M., Ameerun, R. F., Groenewegen, H. J. & Lopes da Silva, F. H. Synaptic plasticity in an in vitro slice preparation of the rat nucleus accumbens. Eur. J. Neurosci. 5, 107–117 (1993)

    Article  CAS  Google Scholar 

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Acknowledgements

We thank P. Kalivas and the members of the Lüscher laboratory for suggestions on the manuscript. This work is supported by the Swiss National Science Foundation (C.L.) and “Synapsy”, a National Competence Center in Research (NCCR) of the Swiss Confederation on the synaptic basis of mental disorders.

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Contributions

V.P. carried out all electrophysiology experiments and was helped by M.T. with the behavioural experiments. C.L. designed the study and wrote the manuscript together with V.P. and M.T.

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Correspondence to Christian Lüscher.

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The authors declare no competing financial interests.

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Pascoli, V., Turiault, M. & Lüscher, C. Reversal of cocaine-evoked synaptic potentiation resets drug-induced adaptive behaviour. Nature 481, 71–75 (2012). https://doi.org/10.1038/nature10709

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