Van den Oever MC et al. (2008) Prefrontal cortex AMPA receptor plasticity is crucial for cue-induced relapse to heroin-seeking. Nat Neurosci [doi: 10.1038/nn.2165]

Inhibition of AMPA receptor endocytosis could help treat addiction to heroin. Van den Oever et al. have used a rat model to demonstrate that the link between re-exposure to preconditioned stimuli and heroin relapse could be explained by endocytosis of the AMPA receptor subunit GluR2, which leads in turn to synaptic depression in the medial prefrontal cortex.

The investigators re-exposed rats to cues that the animals had previously been trained to associate with heroin self-administration. Directly after re-exposure to these cues, AMPA receptor subunits GluR2 and GluR3 and NMDA receptor subtype 2B were downregulated in synaptic membranes of the medial prefrontal cortex, and clathrin-coat assembly protein Ap2m1 was upregulated, as was shown by quantitative proteomics. Re-exposure of rats to heroin-conditioned cues also led to a corresponding reduction in AMPA currents, but not NMDA currents, in pyramidal neurons of the medial prefrontal cortex. Interestingly, rats trained to administer heroin, but that were not re-exposed to cues, had equal AMPA:NMDA current ratios to rats trained to self-administer saline, showing that heroin self-administration in the absence of heroin-conditioned cues does not trigger this mechanism. The cue-induced relapse seems to be dependent on clathrin-mediated AMPA receptor endocytosis in the ventral part of the medial prefrontal cortex, because cue-induced heroin-seeking decreased substantially when clathrin-dependent GluR2 endocytosis was blocked by a mimetic peptide of the GluR2 cytoplasmic tail. Similarly, this peptide was able to block cue-induced synaptic depression.