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Maturation of silent synapses in amygdala-accumbens projection contributes to incubation of cocaine craving

Nature Neuroscience volume 16, pages 1644–1651 (2013)Cite this article

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Abstract

In rat models of drug relapse and craving, cue-induced cocaine seeking progressively increases after withdrawal from the drug. This 'incubation of cocaine craving' is partially mediated by time-dependent adaptations at glutamatergic synapses in nucleus accumbens (NAc). However, the circuit-level adaptations mediating this plasticity remain elusive. We studied silent synapses, often regarded as immature synapses that express stable NMDA receptors with AMPA receptors being either absent or labile, in the projection from the basolateral amygdala to the NAc in incubation of cocaine craving. Silent synapses were detected in this projection during early withdrawal from cocaine. As the withdrawal period progressed, these silent synapses became unsilenced, a process that involved synaptic insertion of calcium-permeable AMPA receptors (CP-AMPARs). In vivo optogenetic stimulation–induced downregulation of CP-AMPARs at amygdala-to-NAc synapses, which re-silenced some of the previously silent synapses after prolonged withdrawal, decreased incubation of cocaine craving. Our findings indicate that silent synapse–based reorganization of the amygdala-to-NAc projection is critical for persistent cocaine craving and relapse after withdrawal.

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Figure 1: Recording of BLA-to-NAc excitatory synapses.
Figure 2: Cocaine self-administration generates silent synapses in the BLA-to-NAc shell projection.
Figure 3: Insertion of CP-AMPARs in BLA-to-NAc synapses after 45 withdrawal days.
Figure 4: Time courses of cocaine incubation, disappearance of silent synapses and emergence of CP-AMPARs after withdrawal from cocaine self-administration.
Figure 5: Blockade of CP-AMPARs re-silences silent synapses in BLA-to-NAc shell projection on withdrawal day 45.
Figure 6: LTD induction at BLA-to-NAc synapses selectively internalizes CP-AMPARs on withdrawal day 45.
Figure 7: Reversing the maturation of silent synapses in the BLA-to-NAc projection reverses incubation of cocaine craving.

Change history

  • 09 October 2013

    In the version of this article initially published online, the Naspm mean data point (black circle) under cocaine in Figure 3i was displaced upward, appearing at a vertical-axis value of ∼1.0. The error has been corrected for the print, PDF and HTML versions of this article.

References

  1. Hunt, W.A., Barnett, L.W. & Branch, L.G. Relapse rates in addiction programs. J. Clin. Psychol. 27, 455–456 (1971).

    Article  CAS  PubMed  Google Scholar 

  2. Gawin, F.H. & Kleber, H.D. Abstinence symptomatology and psychiatric diagnosis in cocaine abusers. Clinical observations. Arch. Gen. Psychiatry 43, 107–113 (1986).

    Article  CAS  PubMed  Google Scholar 

  3. Pickens, C.L. et al. Neurobiology of the incubation of drug craving. Trends Neurosci. 34, 411–420 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Lu, L., Grimm, J.W., Dempsey, J. & Shaham, Y. Cocaine seeking over extended withdrawal periods in rats: different time courses of responding induced by cocaine cues versus cocaine priming over the first 6 months. Psychopharmacology (Berl.) 176, 101–108 (2004).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wolf, M.E. & Tseng, K.Y. Calcium-permeable AMPA receptors in the VTA and nucleus accumbens after cocaine exposure: when, how, and why? Front. Mol. Neurosci. 5, 72 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bossert, J.M., Marchant, N.J., Calu, D.J. & Shaham, Y. The reinstatement model of drug relapse: recent neurobiological findings, emerging research topics, and translational research. Psychopharmacology (Berl.) 229, 453–476 (2013).

    Article  CAS  Google Scholar 

  9. Kalivas, P.W. The glutamate homeostasis hypothesis of addiction. Nat. Rev. Neurosci. 10, 561–572 (2009).

    Article  CAS  PubMed  Google Scholar 

  10. Brown, T.E. et al. A silent synapse–based mechanism for cocaine-induced locomotor sensitization. J. Neurosci. 31, 8163–8174 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Huang, Y.H. et al. In vivo cocaine experience generates silent synapses. Neuron 63, 40–47 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Koya, E. et al. Silent synapses in selectively activated nucleus accumbens neurons following cocaine sensitization. Nat. Neurosci. 15, 1556–1562 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Isaac, J.T., Crair, M.C., Nicoll, R.A. & Malenka, R.C. Silent synapses during development of thalamocortical inputs. Neuron 18, 269–280 (1997).

    Article  CAS  PubMed  Google Scholar 

  14. Kerchner, G.A. & Nicoll, R.A. Silent synapses and the emergence of a postsynaptic mechanism for LTP. Nat. Rev. Neurosci. 9, 813–825 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lee, B.R. & Dong, Y. Cocaine-induced metaplasticity in the nucleus accumbens: silent synapse and beyond. Neuropharmacology 61, 1060–1069 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Belin, D., Jonkman, S., Dickinson, A., Robbins, T.W. & Everitt, B.J. Parallel and interactive learning processes within the basal ganglia: Relevance for the understanding of addiction. Behav. Brain Res. 199, 89–102 (2009).

    Article  PubMed  Google Scholar 

  17. Setlow, B., Holland, P.C. & Gallagher, M. Disconnection of the basolateral amygdala complex and nucleus accumbens impairs appetitive pavlovian second-order conditioned responses. Behav. Neurosci. 116, 267–275 (2002).

    Article  PubMed  Google Scholar 

  18. Stuber, G.D. et al. Excitatory transmission from the amygdala to nucleus accumbens facilitates reward seeking. Nature 475, 377–380 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Pitkanen, A. Connectivity of the rat amygaloid complex. in The Amygdala: a Functional Analysis (ed. J.P. Aggleton) 31–115 (Oxford University Press, Oxford, 2000).

  20. Liao, D., Hessler, N.A. & Malinow, R. Activation of postsynaptically silent synapses during pairing-induced LTP in CA1 region of hippocampal slice. Nature 375, 400–404 (1995).

    Article  CAS  PubMed  Google Scholar 

  21. Mu, P. et al. Exposure to cocaine dynamically regulates the intrinsic membrane excitability of nucleus accumbens neurons. J. Neurosci. 30, 3689–3699 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Otaka, M. et al. Exposure to cocaine regulates inhibitory synaptic transmission in the nucleus accumbens. J. Neurosci. 33, 6753–6758 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Suska, A., Lee, B.R., Huang, Y.H., Dong, Y. & Schluter, O.M. Selective presynaptic enhancement of the prefrontal cortex to nucleus accumbens pathway by cocaine. Proc. Natl. Acad. Sci. USA 110, 713–718 (2013).

    Article  PubMed  Google Scholar 

  24. Lu, L. et al. Role of ventral tegmental area glial cell line–derived neurotrophic factor in incubation of cocaine craving. Biol. Psychiatry 66, 137–145 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Theberge, F.R. et al. Effect of chronic delivery of the Toll-like receptor 4 antagonist (+)-naltrexone on incubation of heroin craving. Biol. Psychiatry 73, 729–737 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lu, L., Grimm, J.W., Hope, B.T. & Shaham, Y. Incubation of cocaine craving after withdrawal: a review of preclinical data. Neuropharmacology 47 (suppl. 1): 214–226 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Sorge, R.E. & Stewart, J. The contribution of drug history and time since termination of drug taking to footshock stress–induced cocaine seeking in rats. Psychopharmacology (Berl.) 183, 210–217 (2005).

    Article  CAS  Google Scholar 

  28. Hollander, J.A. & Carelli, R.M. Cocaine-associated stimuli increase cocaine seeking and activate accumbens core neurons after abstinence. J. Neurosci. 27, 3535–3539 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wolf, M.E. & Ferrario, C.R. AMPA receptor plasticity in the nucleus accumbens after repeated exposure to cocaine. Neurosci. Biobehav. Rev. 35, 185–211 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Durand, G.M., Kovalchuk, Y. & Konnerth, A. Long-term potentiation and functional synapse induction in developing hippocampus. Nature 381, 71–75 (1996).

    Article  CAS  PubMed  Google Scholar 

  31. Ferrario, C.R. et al. Alterations in AMPA receptor subunits and TARPs in the rat nucleus accumbens related to the formation of Ca2+-permeable AMPA receptors during the incubation of cocaine craving. Neuropharmacology 61, 1141–1151 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. McCutcheon, J.E., Wang, X., Tseng, K.Y., Wolf, M.E. & Marinelli, M. Calcium-permeable AMPA receptors are present in nucleus accumbens synapses after prolonged withdrawal from cocaine self-administration but not experimenter-administered cocaine. J. Neurosci. 31, 5737–5743 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. McCutcheon, J.E. et al. Group I mGluR activation reverses cocaine-induced accumulation of calcium-permeable AMPA receptors in nucleus accumbens synapses via a protein kinase C–dependent mechanism. J. Neurosci. 31, 14536–14541 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Purgianto, A. et al. Different adaptations in AMPA receptor transmission in the nucleus accumbens after short versus long access cocaine self-administration regimens. Neuropsychopharmacology 38, 1789–1797 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Cull-Candy, S., Kelly, L. & Farrant, M. Regulation of Ca2+-permeable AMPA receptors: synaptic plasticity and beyond. Curr. Opin. Neurobiol. 16, 288–297 (2006).

    Article  CAS  PubMed  Google Scholar 

  36. 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  PubMed  Google Scholar 

  37. Carroll, R.C., Beattie, E.C., von Zastrow, M. & Malenka, R.C. Role of AMPA receptor endocytosis in synaptic plasticity. Nat. Rev. Neurosci. 2, 315–324 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Waites, C.L., Craig, A.M. & Garner, C.C. Mechanisms of vertebrate synaptogenesis. Annu. Rev. Neurosci. 28, 251–274 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Lonze, B.E. & Ginty, D.D. Function and regulation of CREB family transcription factors in the nervous system. Neuron 35, 605–623 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Barria, A. & Malinow, R. Subunit-specific NMDA receptor trafficking to synapses. Neuron 35, 345–353 (2002).

    Article  CAS  PubMed  Google Scholar 

  41. Robinson, T.E. Structural plasticity associated with exposure to drugs of abuse. Neuropharmacology 47, 33–46 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Russo, S.J. et al. The addicted synapse: mechanisms of synaptic and structural plasticity in nucleus accumbens. Trends Neurosci. 33, 267–276 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Carlezon, W.A. Jr., Duman, R.S. & Nestler, E.J. The many faces of CREB. Trends Neurosci. 28, 436–445 (2005).

    Article  CAS  PubMed  Google Scholar 

  44. Shaham, Y., Shalev, U., Lu, L., De Wit, H. & Stewart, J. The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology (Berl.) 168, 3–20 (2003).

    Article  CAS  Google Scholar 

  45. Marchant, N.J., Li, X. & Shaham, Y. Recent developments in animal models of drug relapse. Curr. Opin. Neurobiol. 23, 675–683 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hollander, J.A. & Carelli, R.M. Abstinence from cocaine self-administration heightens neural encoding of goal-directed behaviors in the accumbens. Neuropsychopharmacology 30, 1464–1474 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. Voorn, P., Vanderschuren, L.J., Groenewegen, H.J., Robbins, T.W. & Pennartz, C.M. Putting a spin on the dorsal-ventral divide of the striatum. Trends Neurosci. 27, 468–474 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Martin, M., Chen, B.T., Hopf, F.W., Bowers, M.S. & Bonci, A. Cocaine self-administration selectively abolishes LTD in the core of the nucleus accumbens. Nat. Neurosci. 9, 868–869 (2006).

    Article  CAS  PubMed  Google Scholar 

  49. Mameli, M. et al. Cocaine-evoked synaptic plasticity: persistence in the VTA triggers adaptations in the NAc. Nat. Neurosci. 12, 1036–1041 (2009).

    Article  CAS  PubMed  Google Scholar 

  50. Loweth, J.A., Tseng, K.Y. & Wolf, M.E. Using metabotropic glutamate receptors to modulate cocaine′s synaptic and behavioral effects: mGluR1 finds a niche. Curr. Opin. Neurobiol. 23, 500–506 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Pilpel, N., Landeck, N., Klugmann, M., Seeburg, P.H. & Schwarz, M.K. Rapid, reproducible transduction of select forebrain regions by targeted recombinant virus injection into the neonatal mouse brain. J. Neurosci. Methods 182, 55–63 (2009).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Marie, H., Morishita, W., Yu, X., Calakos, N. & Malenka, R.C. Generation of silent synapses by acute in vivo expression of CaMKIV and CREB. Neuron 45, 741–752 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Kamboj, S.K., Swanson, G.T. & Cull-Candy, S.G. Intracellular spermine confers rectification on rat calcium-permeable AMPA and kainate receptors. J. Physiol. (Lond.) 486, 297–303 (1995).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank B. Sorg, D. Dietz, R.L. Brown and H. Jansen for technical consultations. This research was supported by the Intramural Research Program of the National Institute on Drug Abuse (Y.S.), extramural funds DA028020 (B.R.L.), DA029565 and DA036303 (Y.H.H.), DA030379 (M.E.W. and Y.D.), DA009621 and DA029099 (M.E.W.), DA007359 and DA014133 (E.J.N.), DA023206, DA031551 and DA034856 (Y.D.) from the National Institute on Drug Abuse, the German Research Foundation through the Cluster of Excellence “Nanoscale Microscopy and Molecular Physiology of the Brain” and grant SCHL592/4 (O.M.S.). The European Neuroscience Institute Göttingen is jointly funded by the Göttingen University Medical School and the Max Planck Society.

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  1. Brian R Lee and Yao-Ying Ma: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Therapeutics, Scripps Research Institute, Jupiter, Florida, USA

    Brian R Lee

  2. Program in Neuroscience, Washington State University, Pullman, Washington, USA

    Brian R Lee, Travis E Brown & Yan Dong

  3. Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Yao-Ying Ma, Mami Otaka, Masago Ishikawa, Peter A Neumann, Nicholas M Graziane, Changyong Guo, Susan R Sesack & Yan Dong

  4. Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Yanhua H Huang & Xiusong Wang

  5. Molecular Neurobiology and Cluster of Excellence “Nanoscale Microscopy and Molecular Physiology of the Brain”, European Neuroscience Institute, Göttingen, Germany

    Anna Suska & Oliver M Schlüter

  6. Fishberg Department of Neuroscience and Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York, USA

    Mary Kay Lobo & Eric J Nestler

  7. Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA

    Marina E Wolf

  8. Behavioral Neuroscience Branch, Intramural Research Program, National Institute on Drug Abuse, US National Institutes of Health, Baltimore, Maryland, USA

    Yavin Shaham

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Contributions

B.R.L., Y.M., Y.H.H., S.R.S., M.E.W., E.J.N., Y.S., O.M.S. and Y.D. contributed to the design of the experiments and the analyses, and the writing of the manuscript. B.R.L., Y.M., X.W., M.O., M.I., P.A.N., N.M.G., T.E.B., A.S., C.G. and M.K.L. conducted the experiments and performed the analyses.

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Correspondence to Yan Dong.

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Integrated supplementary information

Supplementary Figure 1 Summary of saline or cocaine self-administration training data for experiments presented in the main text.

(a) Summarized training data for rats used in Fig. 2C-G. (b) Summarized training data for rats used in Fig. 3A-D. (c) Summarized training data for saline or cocaine for rats used in Fig. 3E-I. (d) Summarized training data for rats used in Fig. 4. (e) Summarized training data for rats used in Fig. 5-6.

Supplementary Figure 2 Additional summary for re-silencing of previously silent synapses by inhibition of CP-AMPARs on withdrawal day 45.

EPSCs elicited by minimal stimulations (recorded at -70 and +50 mV) from BLA-to-NAc synapses 45 days after saline self-administration are shown. A-C Example (a) and trials (b, c) of EPSCs from a saline-withdrawn rat before and during perfusion of Naspm. (d) Summarized results showing that, on withdrawal day 45 day from cocaine self-administration, application of Naspm did not affect the failure rate of EPSCs at either -70 or +50 mV at BLA-to-NAc excitatory synapses. (e) A summary showing that perfusion of Naspm did not affect the level of silent synapses in the BLA-to-NAc shell afferent in saline-experienced rats. This is a control result for Figure 5 in the main text.

Supplementary Figure 3 Additional figure for in vivo LTD-induced reversal of incubation of cocaine craving.

Summarized results showing that cocaine seeking was significantly higher on withdrawal day 45 than on day 1 in sham control rats (left), whereas induction of LTD in the BLA-to-NAc glutamatergic projection reversed the time-dependent increase of cocaine seeking (incubation of craving) (right).

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Supplementary Figures 1–3 (PDF 269 kb)

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Lee, B., Ma, YY., Huang, Y. et al. Maturation of silent synapses in amygdala-accumbens projection contributes to incubation of cocaine craving. Nat Neurosci 16, 1644–1651 (2013). https://doi.org/10.1038/nn.3533

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