1. Department of Neuroscience and,
2. Department of Cellular and Molecular Pharmacology, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, Illinois 60064, USA
3. Behavioral Neuroscience Branch, IRP/NIDA/NIH, 251 Bayview Boulevard, Baltimore, Maryland 21224, USA

Correspondence to: Marina E. Wolf¹ Correspondence and requests for materials should be addressed to M.E.W. (Email: marina.wolf@rosalindfranklin.edu).

Relapse to cocaine use after prolonged abstinence is an important clinical problem. This relapse is often induced by exposure to cues associated with cocaine use. To account for the persistent propensity for relapse, it has been suggested¹ that cue-induced cocaine craving increases over the first several weeks of abstinence and remains high for extended periods. We and others identified an analogous phenomenon in rats that was termed 'incubation of cocaine craving': time-dependent increases in cue-induced cocaine-seeking over the first months after withdrawal from self-administered cocaine^{2, 3, 4}. Cocaine-seeking requires the activation of glutamate projections that excite receptors for -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) in the nucleus accumbens^{5, 6, 7}. Here we show that the number of synaptic AMPA receptors in the accumbens is increased after prolonged withdrawal from cocaine self-administration by the addition of new AMPA receptors lacking glutamate receptor 2 (GluR2). Furthermore, we show that these new receptors mediate the incubation of cocaine craving. Our results indicate that GluR2-lacking AMPA receptors could be a new target for drug development for the treatment of cocaine addiction. We propose that after prolonged withdrawal from cocaine, increased numbers of synaptic AMPA receptors combined with the higher conductance of GluR2-lacking AMPA receptors^{8, 9} causes increased reactivity of accumbens neurons to cocaine-related cues, leading to an intensification of drug craving and relapse.

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