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

Abstract

Relapse to cocaine use after abstinence is often induced by drug-associated cues, but what mediates this reactivity of neurons to these cues is not fully understood. Cocaine-seeking depends on activation of glutamatergic AMPA receptors in the nucleus accumbens. Conrad et al. show that the number of AMPA receptors increases during abstinence in rats, and that the new receptors have a higher conductance. The additional receptors were critical for the increased reactivity of nucleus accumbens neurons to cocaine-related cues, suggesting a novel target for treating relapse. Relapse to cocaine use after abstinence is often induced by drug-associated cues. Cocaine-seeking depends on activation of glutamatergic AMPA receptors in the nucleus accumbens. It is now shown that the number of AMPA receptors increases during abstinence in rodents, and that these new receptors also have a higher conductance. Moreover, these additional receptors were critical for the increased reactivity of nucleus accumbens neurons to cocaine-related cues. 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.