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


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.


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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.

Corresponding author

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).

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