Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Cocaine triggered AMPA receptor redistribution is reversed in vivo by mGluR-dependent long-term depression

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: A single injection of cocaine induces a strong rectification and sensitivity to polyamines in AMPAR EPSCs.
Figure 2: The increase in rectification is paralleled by an increase in the AMPAR:NMDAR ratio.
Figure 3: Disruption of PICK1-GluR2 interaction blocks the increase in both the RI and the AMPAR:NMDAR ratio.
Figure 4: mGluR-LTD depends on rectification and involves a switch of the AMPAR subunit composition.
Figure 5: In vivo application of a positive modulator of mGluR1 reverses the increases in rectification and the AMPAR:NMDAR ratio.

References

  1. Nestler, E.J. Is there a common molecular pathway for addiction? Nat. Neurosci. 8, 1445–1449 (2005).

    Article  CAS  Google Scholar 

  2. Pierce, R.C. & Kumaresan, V. The mesolimbic dopamine system: the final common pathway for the reinforcing effect of drugs of abuse? Neurosci. Biobehav. Rev. 30, 215–238 (2006).

    Article  CAS  Google Scholar 

  3. Robinson, T.E. & Berridge, K.C. The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res. Brain Res. Rev. 18, 247–291 (1993).

    Article  CAS  Google Scholar 

  4. Schenk, S. & Snow, S. Sensitization to cocaine's motor activating properties produced by electrical kindling of the medial prefrontal cortex but not of the hippocampus. Brain Res. 659, 17–22 (1994).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  6. Thomas, M.J. & Malenka, R.C. Synaptic plasticity in the mesolimbic dopamine system. Phil. Trans. R. Soc. Lond. B 358, 815–819 (2003).

    Article  CAS  Google Scholar 

  7. Liu, Q.S., Pu, L. & Poo, M.M. Repeated cocaine exposure in vivo facilitates LTP induction in midbrain dopamine neurons. Nature 437, 1027–1031 (2005).

    Article  CAS  Google Scholar 

  8. 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 

  9. 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 

  10. 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 

  11. Lüscher, C. & Frerking, M. Restless AMPA receptors: implications for synaptic transmission and plasticity. Trends Neurosci. 24, 665–670 (2001).

    Article  Google Scholar 

  12. Carlezon, W.A., Jr. et al. Sensitization to morphine induced by viral-mediated gene transfer. Science 277, 812–814 (1997).

    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. 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 

  15. Dingledine, R., Borges, K., Bowie, D. & Traynelis, S.F. The glutamate receptor ion channels. Pharmacol. Rev. 51, 7–61 (1999).

    CAS  PubMed  Google Scholar 

  16. Faleiro, L.J., Jones, S. & Kauer, J.A. Rapid synaptic plasticity of glutamatergic synapses on dopamine neurons in the ventral tegmental area in response to acute amphetamine injection. Neuropsychopharmacology 29, 2115–2125 (2004).

    Article  CAS  Google Scholar 

  17. Nishimune, A. et al. NSF binding to GluR2 regulates synaptic transmission. Neuron 21, 87–97 (1998).

    Article  CAS  Google Scholar 

  18. Song, I. et al. Interaction of the N-ethylmaleimide-sensitive factor with AMPA receptors. Neuron 21, 393–400 (1998).

    Article  CAS  Google Scholar 

  19. Xia, J., Zhang, X., Staudinger, J. & Huganir, R.L. Clustering of AMPA receptors by the synaptic PDZ domain-containing protein PICK1. Neuron 22, 179–187 (1999).

    Article  CAS  Google Scholar 

  20. Dev, K.K., Nishimune, A., Henley, J.M. & Nakanishi, S. The protein kinase C alpha binding protein PICK1 interacts with short but not long form alternative splice variants of AMPA receptor subunits. Neuropharmacology 38, 635–644 (1999).

    Article  CAS  Google Scholar 

  21. Dong, H. et al. GRIP: a synaptic PDZ domain-containing protein that interacts with AMPA receptors. Nature 386, 279–284 (1997).

    Article  CAS  Google Scholar 

  22. Srivastava, S. et al. Novel anchorage of GluR2/3 to the postsynaptic density by the AMPA receptor-binding protein ABP. Neuron 21, 581–591 (1998).

    Article  CAS  Google Scholar 

  23. Gardner, S.M. et al. Calcium-permeable AMPA receptor plasticity is mediated by subunit-specific interactions with PICK1 and NSF. Neuron 45, 903–915 (2005).

    Article  CAS  Google Scholar 

  24. Liu, S.J. & Cull-Candy, S.G. Subunit interaction with PICK and GRIP controls Ca2+ permeability of AMPARs at cerebellar synapses. Nat. Neurosci. 8, 768–775 (2005).

    Article  CAS  Google Scholar 

  25. Hanley, J.G., Khatri, L., Hanson, P.I. & Ziff, E.B. NSF ATPase and alpha-/beta-SNAPs disassemble the AMPA receptor-PICK1 complex. Neuron 34, 53–67 (2002).

    Article  CAS  Google Scholar 

  26. Terashima, A. et al. Regulation of synaptic strength and AMPA receptor subunit composition by PICK1. J. Neurosci. 24, 5381–5390 (2004).

    Article  CAS  Google Scholar 

  27. Bellone, C. & Lüscher, C. mGluRs induce a long-term depression in the ventral tegmental area that involves a switch of the subunit composition of AMPA receptors. Eur. J. Neurosci. 21, 1280–1288 (2005).

    Article  Google Scholar 

  28. Castillo, P.E., Malenka, R.C. & Nicoll, R.A. Kainate receptors mediate a slow postsynaptic current in hippocampal CA3 neurons. Nature 388, 182–186 (1997).

    Article  CAS  Google Scholar 

  29. Sheng, M. & Kim, M.J. Postsynaptic signaling and plasticity mechanisms. Science 298, 776–780 (2002).

    Article  CAS  Google Scholar 

  30. Daw, M.I. et al. PDZ proteins interacting with C-terminal GluR2/3 are involved in a PKC-dependent regulation of AMPA receptors at hippocampal synapses. Neuron 28, 873–886 (2000).

    Article  CAS  Google Scholar 

  31. Brooks, H., Lebleu, B. & Vives, E. Tat peptide-mediated cellular delivery: back to basics. Adv. Drug Deliv. Rev. 57, 559–577 (2005).

    Article  CAS  Google Scholar 

  32. Schwarze, S.R. & Dowdy, S.F. In vivo protein transduction: intracellular delivery of biologically active proteins, compounds and DNA. Trends Pharmacol. Sci. 21, 45–48 (2000).

    Article  CAS  Google Scholar 

  33. Kauer, J.A. Learning mechanisms in addiction: synaptic plasticity in the ventral tegmental area as a result of exposure to drugs of abuse. Annu. Rev. Physiol. 66, 447–475 (2004).

    Article  CAS  Google Scholar 

  34. Fiorillo, C.D. & Williams, J.T. Glutamate mediates an inhibitory postsynaptic potential in dopamine neurons. Nature 394, 78–82 (1998).

    Article  CAS  Google Scholar 

  35. Knoflach, F. et al. Positive allosteric modulators of metabotropic glutamate 1 receptor: characterization, mechanism of action, and binding site. Proc. Natl. Acad. Sci. USA 98, 13402–13407 (2001).

    Article  CAS  Google Scholar 

  36. 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 

  37. Andrasfalvy, B.K. & Magee, J.C. Changes in AMPA receptor currents following LTP induction on rat CA1 pyramidal neurones. J. Physiol. (Lond.) 559, 543–554 (2004).

    Article  CAS  Google Scholar 

  38. Washburn, M.S., Numberger, M., Zhang, S. & Dingledine, R. Differential dependence on GluR2 expression of three characteristic features of AMPA receptors. J. Neurosci. 17, 9393–9406 (1997).

    Article  CAS  Google Scholar 

  39. Rozov, A., Zilberter, Y., Wollmuth, L.P. & Burnashev, N. Facilitation of currents through rat Ca2+-permeable AMPA receptor channels by activity-dependent relief from polyamine block. J. Physiol. (Lond.) 511, 361–377 (1998).

    Article  CAS  Google Scholar 

  40. Liu, S.Q. & Cull-Candy, S.G. Synaptic activity at calcium-permeable AMPA receptors induces a switch in receptor subtype. Nature 405, 454–458 (2000).

    Article  CAS  Google Scholar 

  41. Chung, H.J., Xia, J., Scannevin, R.H., Zhang, X. & Huganir, R.L. Phosphorylation of the AMPA receptor subunit GluR2 differentially regulates its interaction with PDZ domain-containing proteins. J. Neurosci. 20, 7258–7267 (2000).

    Article  CAS  Google Scholar 

  42. Kim, C.H., Chung, H.J., Lee, H.K. & Huganir, R.L. Interaction of the AMPA receptor subunit GluR2/3 with PDZ domains regulates hippocampal long-term depression. Proc. Natl. Acad. Sci. USA 98, 11725–11730 (2001).

    Article  CAS  Google Scholar 

  43. Perez, J.L. et al. PICK1 targets activated protein kinase Calpha to AMPA receptor clusters in spines of hippocampal neurons and reduces surface levels of the AMPA-type glutamate receptor subunit 2. J. Neurosci. 21, 5417–5428 (2001).

    Article  CAS  Google Scholar 

  44. Tanaka, H., Grooms, S.Y., Bennett, M.V. & Zukin, R.S. The AMPAR subunit GluR2: still front and center-stage(1). Brain Res. 886, 190–207 (2000).

    Article  CAS  Google Scholar 

  45. Hartmann, B. et al. The AMPA receptor subunits GluR-A and GluR-B reciprocally modulate spinal synaptic plasticity and inflammatory pain. Neuron 44, 637–650 (2004).

    Article  CAS  Google Scholar 

  46. Szumlinski, K.K., Toda, S., Middaugh, L.D., Worley, P.F. & Kalivas, P.W. Evidence for a relationship between Group 1 mGluR hypofunction and increased cocaine and ethanol sensitivity in Homer2 null mutant mice. Ann. NY Acad. Sci. 1003, 468–471 (2003).

    Article  Google Scholar 

  47. Chiamulera, C. et al. Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice. Nat. Neurosci. 4, 873–874 (2001).

    Article  CAS  Google Scholar 

  48. Johnson, S.W. & North, R.A. Two types of neurone in the rat ventral tegmental area and their synaptic inputs. J. Physiol. (Lond.) 450, 455–468 (1992).

    Article  CAS  Google Scholar 

  49. Neuhoff, H., Neu, A., Liss, B. & Roeper, J. I(h) channels contribute to the different functional properties of identified dopaminergic subpopulations in the midbrain. J. Neurosci. 22, 1290–1302 (2002).

    Article  CAS  Google Scholar 

  50. Cruz, H.G. et al. Bi-directional effects of GABA(B) receptor agonists on the mesolimbic dopamine system. Nat. Neurosci. 7, 153–159 (2004).

    Article  CAS  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Christian Lüscher.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Representative examples of AMPAR-EPSCs recorded in drug-naïve rat and mouse. (PDF 797 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1682

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing