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

Kelly L. Conrad, Kuei Y. Tseng, Jamie L. Uejima, Jeremy M. Reimers, Li Jun Heng, Yavin Shaham, Michela Marinelli, Marina Wolf

Research output: Contribution to journalArticle

522 Citations (Scopus)

Abstract

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 suggested 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. 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 accumbens. 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 causes increased reactivity of accumbens neurons to cocaine-related cues, leading to an intensification of drug craving and relapse.

Original languageEnglish (US)
Pages (from-to)118-121
Number of pages4
JournalNature
Volume454
Issue number7200
DOIs
StatePublished - Jul 3 2008
Externally publishedYes

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AMPA Receptors
Glutamate Receptors
Cocaine
Cues
Recurrence
Neurotransmitter Receptor
Craving
(2-azidomethyl)phenylacetyl
Isoxazoles
Cocaine-Related Disorders
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Self Administration
Nucleus Accumbens
Pharmaceutical Preparations
Glutamic Acid
Neurons

ASJC Scopus subject areas

  • General

Cite this

Conrad, K. L., Tseng, K. Y., Uejima, J. L., Reimers, J. M., Heng, L. J., Shaham, Y., ... Wolf, M. (2008). Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving. Nature, 454(7200), 118-121. https://doi.org/10.1038/nature06995

Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving. / Conrad, Kelly L.; Tseng, Kuei Y.; Uejima, Jamie L.; Reimers, Jeremy M.; Heng, Li Jun; Shaham, Yavin; Marinelli, Michela; Wolf, Marina.

In: Nature, Vol. 454, No. 7200, 03.07.2008, p. 118-121.

Research output: Contribution to journalArticle

Conrad, KL, Tseng, KY, Uejima, JL, Reimers, JM, Heng, LJ, Shaham, Y, Marinelli, M & Wolf, M 2008, 'Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving', Nature, vol. 454, no. 7200, pp. 118-121. https://doi.org/10.1038/nature06995
Conrad KL, Tseng KY, Uejima JL, Reimers JM, Heng LJ, Shaham Y et al. Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving. Nature. 2008 Jul 3;454(7200):118-121. https://doi.org/10.1038/nature06995
Conrad, Kelly L. ; Tseng, Kuei Y. ; Uejima, Jamie L. ; Reimers, Jeremy M. ; Heng, Li Jun ; Shaham, Yavin ; Marinelli, Michela ; Wolf, Marina. / Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving. In: Nature. 2008 ; Vol. 454, No. 7200. pp. 118-121.
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