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Nature Neuroscience 11, 1053–1058 (1 September 2008) | doi:10.1038/nn.2165

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

Michel C Van den Oever , Natalia A Goriounova , Ka Wan Li , Roel C Van der Schors , Rob Binnekade , Anton N M Schoffelmeer , Huibert D Mansvelder , August B Smit , Sabine Spijker & Taco J De Vries

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.