Sutton MA, Schmidt EF, Choi KH, Schad CA, Whisler K, Simmons D et al. Extinction-induced upregulation in AMPA receptors reduces cocaine-seeking behavior. Nature 421: 70-75

Division of Molecular Psychiatry and the Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Nature (Impact Factor: 41.46). 02/2003; 421(6918):70-5. DOI: 10.1038/nature01249
Source: PubMed


Cocaine addiction is thought to involve persistent neurobiological changes that facilitate relapse to drug use despite efforts to abstain. But the propensity for relapse may be reduced by extinction training--a form of inhibitory learning that progressively reduces cocaine-seeking behaviour in the absence of cocaine reward. Here we show that extinction training during withdrawal from chronic cocaine self-administration induces experience-dependent increases in the GluR1 and GluR2/3 subunits of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate) glutamate receptors in the nucleus accumbens shell, a brain region that is critically involved in cocaine reward. Increases in the GluR1 subunit are positively associated with the level of extinction achieved during training, suggesting that GluR1 may promote extinction of cocaine seeking. Indeed, viral-mediated overexpression of both GluR1 and GluR2 in nucleus accumbens shell neurons facilitates extinction of cocaine- but not sucrose-seeking responses. A single extinction training session, when conducted during GluR subunit overexpression, attenuates stress-induced relapse to cocaine seeking even after GluR overexpression declines. Our findings indicate that extinction-induced plasticity in AMPA receptors may facilitate control over cocaine seeking by restoring glutamatergic tone in the nucleus accumbens, and may reduce the propensity for relapse under stressful situations in prolonged abstinence.

Download full-text


Available from: David W Self, Nov 23, 2015
    • "S. Nuutinen et al. / Neuropharmacology xxx (2015) 1e8 3 Please cite this article in press as: Nuutinen, S., et al., Histamine H3 receptor antagonist decreases cue-induced alcohol reinstatement in mice, Neuropharmacology (2015), process during repeated extinction phases might make it difficult to compare drug effects from different experimental days. Furthermore , repeated training of extinction has previously been shown to decrease the propensity for a relapse of extinguished cocaineseeking behavior in rats (Sutton et al., 2003). A within-subject variability of less than 10% in active lever presses between the baseline reinstatement tests was allowed. "
    [Show abstract] [Hide abstract]
    ABSTRACT: We have earlier found that the histamine H3 receptor (H3R) antagonism diminishes motivational aspects of alcohol reinforcement in mice. Here we studied the role of H3Rs in cue-induced reinstatement of alcohol seeking in C57BL/6J mice using two different H3R antagonists. Systemic administration of H3R antagonists attenuated cue-induced alcohol seeking suggesting that H3R antagonists may reduce alcohol craving. To understand how alcohol affects dopamine and histamine release, a microdialysis study was performed on C57BL/6J mice and the levels of histamine, dopamine and dopamine metabolites were measured in the nucleus accumbens. Alcohol administration was combined with an H3R antagonist pretreatment to reveal whether modulation of H3R affects the effects of alcohol on neurotransmitter release. Alcohol significantly increased the release of dopamine in the nucleus accumbens but did not affect histamine release. Pretreatment with H3R antagonist ciproxifan did not modify the effect of alcohol on dopamine release. However, histamine release was markedly increased with ciproxifan. In conclusion, our findings demonstrate that H3R antagonism attenuates cue-induced reinstatement of alcohol seeking in mice. Alcohol alone does not affect histamine release in the nucleus accumbens but H3R antagonist instead increases histamine release significantly suggesting that the mechanism by which H3R antagonist inhibits alcohol seeking found in the present study and the decreased alcohol reinforcement, reward and consumption found earlier might include alterations in the histaminergic neurotransmission in the nucleus accumbens. These findings imply that selective antagonists of H3Rs could be a therapeutic strategy to prevent relapse and possibly diminish craving to alcohol use. Copyright © 2015. Published by Elsevier Ltd.
    No preview · Article · Jun 2015 · Neuropharmacology
  • Source
    • "GluR1 expression is not altered in either structure or any groups. These results are unexpected as previous research, using a long-access model of self-administration, found an increase in GluR1 expression in the NAc shell after 1 week of extinction with (Sutton et al. 2003) or without discrete cues (Self et al. 2004) and an increase in GluN2B expression in the PFC following 13 days of context extinction (Tang et al. 2004). Furthermore, using a short-access model, GluR1 expression is increased in the vmPFC, but not NAc, following a single 2-h extinction session with discrete cues (Nic Dhonnchadha et al. 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Rationale Extinction of drug seeking is facilitated by NMDA receptor (NMDAr) agonists, but it remains unclear whether extinction is dependent on NMDAr activity. Objectives We investigated the necessity of NMDArs for extinction of cocaine seeking and whether extinction altered NMDAr expression within extinction-related neuroanatomical loci. Methods Rats were trained to lever press for i.v. infusions of cocaine or sucrose reinforcement prior to extinction training or withdrawal. Results Administration of the NMDAr competitive antagonist CPP prior to four brief extinction sessions impaired subsequent extinction retention. In contrast, administration of the NMDAr coagonist D-serine after four brief extinction sessions attenuated lever pressing during subsequent extinction, indicative of facilitated consolidation of extinction. Furthermore, expression of the NMDAr subunits, GluN2A and GluN2B, was not altered in the ventromedial prefrontal cortex. However, both GluN2A and GluN2B subunit expression in the nucleus accumbens increased following cocaine self-administration, and this increased expression was relatively resistant to modulation by extinction. Conclusions Our findings demonstrate that extinction of cocaine seeking is bidirectionally mediated by NMDArs and suggest that selective modulation of NMDAr activity could facilitate extinction-based therapies for treatment of cocaine abuse.
    Full-text · Article · May 2014 · Psychopharmacology
  • Source
    • "aLumiere et al . 2010 ; Peters et al . 2008 ) . Consolidated extinction learning is also associated with sev - eral neurobiological changes within the mesocorticolimbic system such as altered expression of tyrosine hydroxylase , glutamate receptors , and scaffolding proteins at glutamate synapses ( Knackstedt et al . 2010b ; Schmidt et al . 2001 ; Sutton et al . 2003 ) . Both A1ARs and A2ARs are highly localized to the brain areas within the mesocorticolimbic system such as the NAc where they may influence extinction - induced neurobiological effects to directly influ - ence extinction responding and subsequent reinstatement . We hypothesize that A1ARs and A2ARs situated on pre - synaptic terminals "
    [Show abstract] [Hide abstract]
    ABSTRACT: Adenosine receptor stimulation and blockade have been shown to modulate a variety of cocaine-related behaviors. These studies identify the direct effects of adenosine receptor stimulation on cocaine seeking during extinction training and the persistent effects on subsequent reinstatement to cocaine seeking. Rats self-administered cocaine on a fixed ratio one schedule in daily sessions over 3 weeks. Following a 1-week withdrawal, the direct effects of adenosine receptor modulation were tested by administering the adenosine A1 receptor agonist, N(6)-cyclopentyladenosine (CPA, 0.03 and 0.1 mg/kg), the adenosine A2A agonist, CGS 21680 (0.03 and 0.1 mg/kg), the presynaptic adenosine A2A receptor antagonist, SCH 442416 (0.3, 1, and 3 mg/kg), or vehicle prior to each of six daily extinction sessions. The persistent effects of adenosine receptor modulation during extinction training were subsequently tested on reinstatement to cocaine seeking induced by cues, cocaine, and the dopamine D2 receptor agonist, quinpirole. All doses of CPA and CGS 21680 impaired initial extinction responding; however, only CPA treatment during extinction produced persistent impairment in subsequent cocaine- and quinpirole-induced seeking. Dissociating CPA treatment from extinction did not alter extinction responding or subsequent reinstatement. Administration of SCH 442416 had no direct effects on extinction responding but produced dose-dependent persistent impairment of cocaine- and quinpirole-induced seeking. These findings demonstrate that adenosine A1 or A2A receptor stimulation directly impair extinction responding. Interestingly, adenosine A1 receptor stimulation or presynaptic adenosine A2A receptor blockade during extinction produces lasting changes in relapse susceptibility.
    Full-text · Article · Feb 2014 · Psychopharmacology
Show more