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 454: 118-121

Department of Neuroscience, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, Illinois 60064, USA.
Nature (Impact Factor: 41.46). 08/2008; 454(7200):118-21. DOI: 10.1038/nature06995
Source: PubMed


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 alpha-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.

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Available from: Jeremy M. Reimers, Feb 27, 2014
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    • "Cue-induced drug seeking has been shown to peak around 2–3 months of withdrawal in both rats (Grimm et al. 2001; Lu et al. 2004) and humans (Wang et al. 2013; Li et al. 2014), and greater drug seeking during late vs. early withdrawal was found using a range of reinforcers including cocaine (Gawin and Kleber 1986; Grimm et al. 2003; Shaham 2002), nicotine (Abdolahi et al. 2010; Bedi et al. 2011), methamphetamine (Shepard et al. 2004; Wang et al. 2013), heroin (Shalev et al. 2001), alcohol (Bienkowski et al. 2004; Li et al. 2014), and sucrose (Grimm et al. 2005). As it may enhance vulnerability to relapse after an extended withdrawal period, incubation of drug seeking is an important factor to consider in designing treatment strategies for drug abuse (Lu et al. 2004; Conrad et al. 2008; Pickens et al. 2011; Chauvet et al. 2012). Thus far, however, few investigations have examined treatments to reduce or eliminate the incubation of cue-induced drug seeking. "
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    ABSTRACT: Recent research has demonstrated that aerobic exercise can attenuate craving for drugs of abuse and reduce escalation and reinstatement of drug-seeking behavior in animal models. The present study examined the effects of aerobic exercise on the development of the incubation of cocaine-seeking behavior or the progressive increase in cocaine seeking over a protracted withdrawal period from cocaine self-administration. Female rats were trained to self-administer cocaine (0.4 mg/kg/inf) during daily 6-h sessions for 10 days. Subsequently, access to cocaine and cocaine-paired cues was discontinued during a 3- or 30-day withdrawal period when rats had access to either a locked or unlocked running wheel. At the end of the withdrawal period, rats were reintroduced to the operant conditioning chamber and reexposed to cocaine-paired cues to examine cocaine-seeking behavior under extinction conditions. Rats with access to a locked running wheel during 30 days of withdrawal had significantly greater cue-induced cocaine-seeking behavior than rats that had access to an unlocked running wheel for 30 days. Further, there was robust incubation of cocaine seeking in rats with access to a locked running wheel as cocaine seeking was notably elevated at 30 vs. 3 days of withdrawal. However, cocaine-seeking behavior did not differ between rats with access to an unlocked running wheel for 30 vs. 3 days, indicating that incubation of cocaine seeking was suppressed following access to exercise for 30 days. Aerobic exercise during extended withdrawal from cocaine self-administration decreased incubation of cue-induced cocaine-seeking behavior and may reduce vulnerability to relapse.
    Full-text · Article · Jul 2015 · Psychopharmacology
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    • "GluA2/GluA3 traffic constitutively to synapses, while trafficking of GluA1-containing receptors is dependent on synaptic activity (Barry and Ziff, 2002; Greger et al., 2007). AMPAR trafficking in NAc has been implicated in sensitization, craving, and relapse to cocaine seeking (Cornish et al., 1999; Cornish and Kalivas, 2000; Boudreau and Wolf, 2005; Conrad et al., 2008; Famous et al., 2008; Wolf and Ferrario, 2010, pp. 65–72; Xie et al., 2011), and Ca 2+ -permeable AMPARs in NAc have been implicated in the enhanced rewarding effects of amphetamine and D1 receptor stimulation in FR rats (Carr et al., 2010; Peng et al., 2014). "
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    ABSTRACT: Weight-loss dieting often leads to loss of control, rebound weight gain, and is a risk factor for binge pathology. Based on findings that food restriction (FR) upregulates sucrose-induced trafficking of glutamatergic AMPA receptors to the nucleus accumbens (NAc) postsynaptic density (PSD), this study was an initial test of the hypothesis that episodic "breakthrough" intake of forbidden food during dieting interacts with upregulated mechanisms of synaptic plasticity to increase reward-driven feeding. Ad libitum (AL) fed and FR subjects consumed a limited amount of 10% sucrose, or had access to water, every other day for ten occasions. Beginning three weeks after return of FR rats to AL feeding, when 24-hour chow intake and rate of body weight gain had normalized, subjects with a history of sucrose intake during FR consumed more sucrose during a four week intermittent access protocol than the two AL groups and the group that had access to water during FR. In an experiment that substituted noncontingent administration of d-amphetamine for sucrose, FR subjects displayed an enhanced locomotor response during active FR but a blunted response, relative to AL subjects, during recovery from FR. This result suggests that the enduring increase in sucrose consumption is unlikely to be explained by residual enhancing effects of FR on dopamine signaling. In a biochemical experiment which paralleled the sucrose behavioral experiment, rats with a history of sucrose intake during FR displayed increased abundance of pSer845-GluA1, GluA2, and GluA3 in the NAc PSD relative to rats with a history of FR without sucrose access and rats that had been AL throughout, whether they had a history of episodic sucrose intake or not. A history of FR, with or without a history of sucrose intake, was associated with increased abundance of GluA1. A terminal 15-min bout of sucrose intake produced a further increase in pSer845-GluA1 and GluA2 in subjects with a history of sucrose intake during FR. Generally, neither a history of sucrose intake nor a terminal bout of sucrose intake affected AMPA receptor abundance in the NAc PSD of AL subjects. Together, these results are consistent with the hypothesis, but the functional contribution of increased synaptic incorporation of AMPA receptors remains to be established. Copyright © 2015. Published by Elsevier Ltd.
    Full-text · Article · Mar 2015 · Neuroscience
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    • "Halbout et al. (2014) examined neuroadaptations associated with incubation after a single session. They found several similarities compared with previous findings about incubation after extended access (Conrad et al. 2008; Loweth et al. 2014). For example, they showed that AMPA receptor availability is significantly increased in NAc shell on withdrawal day 43. "
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    ABSTRACT: Cue-induced drug craving progressively increases after prolonged withdrawal from drug self-administration in laboratory animals, a behavioral phenomenon termed 'incubation of drug craving.' Studies over the years have revealed several important neural mechanisms contributing to incubation of drug craving. In this mini-review, we first discuss three excellent Addiction Biology publications on incubation of drug craving in both human and laboratory animals. We then review several key publications from the past year on behavioral and mechanistic findings related to incubation of drug craving. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.
    Full-text · Article · Dec 2014 · Addiction Biology
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