Prefrontal cortex AMPA receptor plasticity is crucial for cue-induced relapse to heroin-seeking

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Associative learning processes have an important role in the initiation and persistence of heroin-seeking. Here we show in a rat self-administration model that reexposure to cues previously associated with heroin results in downregulation of AMPA receptor subunit GluR2 and concomitant upregulation of clathrin-coat assembly protein AP2m1 in synaptic membranes of the medial prefrontal cortex (mPFC). Reduced AMPA receptor expression in synaptic membranes was associated with a decreased AMPA/NMDA current ratio and increased rectification index in mPFC pyramidal neurons. Systemic or ventral (but not dorsal) mPFC injections of a peptide inhibiting GluR2 endocytosis attenuated both the rectification index and cue-induced relapse to heroin-seeking, without affecting sucrose-seeking. We conclude that GluR2 receptor endocytosis and the resulting synaptic depression in ventral mPFC are crucial for cue-induced relapse to heroin-seeking. As reexposure to conditioned stimuli is a major cause for heroin relapse, inhibition of GluR2 endocytosis may provide a new target for the treatment of heroin addiction.

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Figure 1: Heroin acquisition and relapse.
Figure 2: Protein changes after cue-induced relapse to heroin-seeking.
Figure 3: Cue-induced heroin-seeking alters synaptic strength.
Figure 4: Blockade of GluR2 endocytosis attenuates cue-induced heroin-seeking.
Figure 5: TAT-GluR23Y does not impair relapse to sucrose-seeking.


  1. 1

    O'Brien, C.P., Ehrman, R.N. & Ternes, J.W. Classical Conditioning in Human Opioid Dependence 329–356 (Academic Press, Orlando, 1986).

  2. 2

    Everitt, B.J. & Wolf, M.E. Psychomotor stimulant addiction: a neural systems perspective. J. Neurosci. 22, 3312–3320 (2002).

  3. 3

    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).

  4. 4

    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).

  5. 5

    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).

  6. 6

    Chklovskii, D.B., Mel, B.W. & Svoboda, K. Cortical rewiring and information storage. Nature 431, 782–788 (2004).

  7. 7

    Wikler, A. Dynamics of drug dependence. Implications of a conditioning theory for research and treatment. Arch. Gen. Psychiatry 28, 611–616 (1973).

  8. 8

    Koya, E. et al. Enhanced cortical and accumbal molecular reactivity associated with conditioned heroin, but not sucrose-seeking behaviour. J. Neurochem. 98, 905–915 (2006).

  9. 9

    Schmidt, E.D., Voorn, P., Binnekade, R., Schoffelmeer, A.N. & De Vries, T.J. Differential involvement of the prelimbic cortex and striatum in conditioned heroin and sucrose seeking following long-term extinction. Eur. J. Neurosci. 22, 2347–2356 (2005).

  10. 10

    Epstein, D.H., Preston, K.L., Stewart, J. & Shaham, Y. Toward a model of drug relapse: an assessment of the validity of the reinstatement procedure. Psychopharmacology (Berl.) 189, 1–16 (2006).

  11. 11

    McLaughlin, J. & See, R.E. Selective inactivation of the dorsomedial prefrontal cortex and the basolateral amygdala attenuates conditioned-cued reinstatement of extinguished cocaine-seeking behavior in rats. Psychopharmacology (Berl.) 168, 57–65 (2003).

  12. 12

    Kalivas, P.W., Volkow, N. & Seamans, J. Unmanageable motivation in addiction: a pathology in prefrontal-accumbens glutamate transmission. Neuron 45, 647–650 (2005).

  13. 13

    Hu, J. et al. Optimized proteomic analysis of a mouse model of cerebellar dysfunction using amine-specific isobaric tags. Proteomics 6, 4321–4334 (2006).

  14. 14

    Liu, T. et al. A multiplexed proteomics approach to differentiate neurite outgrowth patterns. J. Neurosci. Methods 158, 22–29 (2006).

  15. 15

    Li, K.W. et al. Quantitative proteomics and protein network analysis of hippocampal synapses of CaMKIIα mutant mice. J. Proteome Res. 6, 3127–3133 (2007).

  16. 16

    Man, H.Y. et al. Regulation of AMPA receptor-mediated synaptic transmission by clathrin-dependent receptor internalization. Neuron 25, 649–662 (2000).

  17. 17

    Kastning, K. et al. Molecular determinants for the interaction between AMPA receptors and the clathrin adaptor complex AP-2. Proc. Natl. Acad. Sci. USA 104, 2991–2996 (2007).

  18. 18

    Lee, S.H., Liu, L., Wang, Y.T. & Sheng, M. Clathrin adaptor AP2 and NSF interact with overlapping sites of GluR2 and play distinct roles in AMPA receptor trafficking and hippocampal LTD. Neuron 36, 661–674 (2002).

  19. 19

    Mierau, S.B., Meredith, R.M., Upton, A.L. & Paulsen, O. Dissociation of experience-dependent and -independent changes in excitatory synaptic transmission during development of barrel cortex. Proc. Natl. Acad. Sci. USA 101, 15518–15523 (2004).

  20. 20

    Myme, C.I., Sugino, K., Turrigiano, G.G. & Nelson, S.B. The NMDA-to-AMPA ratio at synapses onto layer 2/3 pyramidal neurons is conserved across prefrontal and visual cortices. J. Neurophysiol. 90, 771–779 (2003).

  21. 21

    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).

  22. 22

    Hayashi, T. & Huganir, R.L. Tyrosine phosphorylation and regulation of the AMPA receptor by SRC family tyrosine kinases. J. Neurosci. 24, 6152–6160 (2004).

  23. 23

    Brebner, K. et al. Nucleus accumbens long-term depression and the expression of behavioral sensitization. Science 310, 1340–1343 (2005).

  24. 24

    Ahmadian, G. et al. Tyrosine phosphorylation of GluR2 is required for insulin-stimulated AMPA receptor endocytosis and LTD. EMBO J. 23, 1040–1050 (2004).

  25. 25

    Verdoorn, T.A., Burnashev, N., Monyer, H., Seeburg, P.H. & Sakmann, B. Structural determinants of ion flow through recombinant glutamate receptor channels. Science 252, 1715–1718 (1991).

  26. 26

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

  27. 27

    Malinow, R. & Malenka, R.C. AMPA receptor trafficking and synaptic plasticity. Annu. Rev. Neurosci. 25, 103–126 (2002).

  28. 28

    Hyman, S.E. Addiction: a disease of learning and memory. Am. J. Psychiatry 162, 1414–1422 (2005).

  29. 29

    Kelley, A.E. Memory and addiction: shared neural circuitry and molecular mechanisms. Neuron 44, 161–179 (2004).

  30. 30

    Nestler, E.J. From neurobiology to treatment: progress against addiction. Nat. Neurosci. 5 Suppl: 1076–1079 (2002).

  31. 31

    Mansvelder, H.D. & McGehee, D.S. Long-term potentiation of excitatory inputs to brain reward areas by nicotine. Neuron 27, 349–357 (2000).

  32. 32

    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).

  33. 33

    Chowdhury, S. et al. Arc/Arg3.1 interacts with the endocytic machinery to regulate AMPA receptor trafficking. Neuron 52, 445–459 (2006).

  34. 34

    Rial Verde, E.M., Lee-Osbourne, J., Worley, P.F., Malinow, R. & Cline, H.T. Increased expression of the immediate-early gene arc/arg3.1 reduces AMPA receptor-mediated synaptic transmission. Neuron 52, 461–474 (2006).

  35. 35

    McFarland, K., Davidge, S.B., Lapish, C.C. & Kalivas, P.W. Limbic and motor circuitry underlying footshock-induced reinstatement of cocaine-seeking behavior. J. Neurosci. 24, 1551–1560 (2004).

  36. 36

    McFarland, K., Lapish, C.C. & Kalivas, P.W. Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behavior. J. Neurosci. 23, 3531–3537 (2003).

  37. 37

    Peters, J., LaLumiere, R.T. & Kalivas, P.W. Infralimbic prefrontal cortex is responsible for inhibiting cocaine seeking in extinguished rats. J. Neurosci. 28, 6046–6053 (2008).

  38. 38

    Koya, E. et al. Role of ventral medial prefrontal cortex in incubation of cocaine craving. Neuropharmacology, doi:10.1016/j.neuropharm.2008.04.022 (8 May 2008).

  39. 39

    Rogers, J.L., Ghee, S. & See, R.E. The neural circuitry underlying reinstatement of heroin-seeking behavior in an animal model of relapse. Neuroscience 151, 579–588 (2008).

  40. 40

    LaLumiere, R.T. & Kalivas, P.W. Glutamate release in the nucleus accumbens core is necessary for heroin seeking. J. Neurosci. 28, 3170–3177 (2008).

  41. 41

    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).

  42. 42

    Thierry, A.M., Stinus, L., Blanc, G. & Glowinski, J. Some evidence for the existence of dopaminergic neurons in the rat cortex. Brain Res. 50, 230–234 (1973).

  43. 43

    McDonald, A.J. Organization of amygdaloid projections to the mediodorsal thalamus and prefrontal cortex: a fluorescence retrograde transport study in the rat. J. Comp. Neurol. 262, 46–58 (1987).

  44. 44

    Heidbreder, C.A. & Groenewegen, H.J. The medial prefrontal cortex in the rat: evidence for a dorso-ventral distinction based upon functional and anatomical characteristics. Neurosci. Biobehav. Rev. 27, 555–579 (2003).

  45. 45

    Fuchs, R.A. & See, R.E. Basolateral amygdala inactivation abolishes conditioned stimulus- and heroin-induced reinstatement of extinguished heroin-seeking behavior in rats. Psychopharmacology (Berl.) 160, 425–433 (2002).

  46. 46

    Bossert, J.M., Liu, S.Y., Lu, L. & Shaham, Y. A role of ventral tegmental area glutamate in contextual cue-induced relapse to heroin seeking. J. Neurosci. 24, 10726–10730 (2004).

  47. 47

    Zhou, W. et al. Role of acetylcholine transmission in nucleus accumbens and ventral tegmental area in heroin-seeking induced by conditioned cues. Neuroscience 144, 1209–1218 (2007).

  48. 48

    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).

  49. 49

    Bossert, J.M., Gray, S.M., Lu, L. & Shaham, Y. Activation of group II metabotropic glutamate receptors in the nucleus accumbens shell attenuates context-induced relapse to heroin seeking. Neuropsychopharmacology 31, 2197–2209 (2006).

  50. 50

    Couey, J.J. et al. Distributed network actions by nicotine increase the threshold for spike-timing-dependent plasticity in prefrontal cortex. Neuron 54, 73–87 (2007).

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The authors thank W. de Vries, H. Raasø, M. Stegeman and Y. Gouwenberg for technical assistance and Y. Shaham for valuable comments on the manuscript. This work was supported by grants from the Center for Medical Systems Biology (to M.C.V.d.O., S.S., R.C.V.d.S., K.W.L. and A.B.S.) and the Netherlands Organization for Scientific Research (to N.A.G. and H.D.M.).

Author information

M.C.V.d.O. and N.A.G. contributed equally to this work. M.C.V.d.O., A.N.M.S., H.D.M., A.B.S., S.S. and T.J.D.V. designed the experiments. M.C.V.d.O. and R.B. executed the behavior experiments. M.C.V.d.O. and T.J.D.V. analyzed the behavioral data. M.C.V.d.O., K.W.L., R.C.V.d.S., R.B. and S.S. executed the molecular experiments. M.C.V.d.O. and S.S. analyzed the molecular data. N.A.G. executed the electrophysiology experiments. N.A.G. and H.D.M. analyzed the electrophysiology data. M.C.V.d.O., A.B.S., H.D.M., T.J.D.V. and S.S. wrote the manuscript.

Correspondence to Sabine Spijker.

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Van den Oever, M., Goriounova, N., Wan Li, K. et al. Prefrontal cortex AMPA receptor plasticity is crucial for cue-induced relapse to heroin-seeking. Nat Neurosci 11, 1053–1058 (2008) doi:10.1038/nn.2165

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