Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving


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 cocaine2,3,4. Cocaine-seeking requires the activation of glutamate projections that excite receptors for α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) in the nucleus accumbens5,6,7. 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 receptors8,9 causes increased reactivity of accumbens neurons to cocaine-related cues, leading to an intensification of drug craving and relapse.

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Figure 1: Time-dependent increases in cue-induced cocaine-seeking (incubation of cocaine craving).
Figure 2: Accumbens GluR1 and GluR3 expression increase after withdrawal from cocaine self-administration.
Figure 3: GluR2-lacking AMPA receptors are detected in accumbens neurons after prolonged withdrawal from self-administration of cocaine.
Figure 4: Enhanced cue-induced cocaine-seeking after prolonged withdrawal from cocaine self-administration is inhibited by blockade of GluR2-lacking AMPA receptors.

Change history

  • 03 July 2008

    In the AOP version of this paper, the sentence ‘Scaling-induced increases in GluR1 have been reported to occur through increased dendritic GluR1 synthesis26 as well as decreased GluR1 protein stability27.’ should have read ‘ well as increased GluR1 protein stability27.’. This was corrected for print on 3 July 2008.


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We thank R. J. Wenthold for help in establishing quantitative co-immunoprecipitation methods used in Supplementary Fig. 2. This work was supported by US Public Health Service grants DA09621, DA015835, DA00453 and NARSAD (M.E.W.), DA020654 (M.M.), predoctoral National Research Service Award DA021488 (K.L.C.), Rosalind Franklin University of Medicine and Science start-up funds (K.Y.T.) and the Intramural Research Program of the National Institute on Drug Abuse (Y.S.).

Author Contributions K.L.C., M.M. and M.E.W. were responsible for overall study design. K.L.C. conducted and analysed cocaine self-administration experiments (except the Naspm experiment) and protein crosslinking studies. M.M. trained K.L.C. in drug self-administration procedures and helped with these experiments. J.M.R. conducted and analysed co-immunoprecipitation experiments. K.Y.T. designed electrophysiological experiments, L.J.H. conducted them, and K.Y.T. analysed the data. Y.S. and K.L.C. designed the Naspm behavioural experiment, J.L.U. performed it, and Y.S. and J.L.U. analysed the data. K.L.C., Y.S. and M.E.W. wrote the paper with the help of the other authors.

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Correspondence to Marina E. Wolf.

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Supplementary Information

The file contains Supplementary Figures 1-8 and Legends; Supplementary Methods with additional references. The Supplementary Figures show additional experimental data in support of the manuscript's conclusions. The Supplementary Methods provide detailed descriptions of the procedures. (PDF 391 kb)

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Conrad, K., Tseng, K., Uejima, J. et al. Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving. Nature 454, 118–121 (2008) doi:10.1038/nature06995

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