Disrupting Reconsolidation of Drug Memories Reduces Cocaine-Seeking Behavior

Lee, Jonathan; Ciano, Patricia Di; Thomas, Kerrie L.; Everitt, Barry J.

doi:10.1016/j.neuron.2005.08.007

Cited by 366 publications

(404 citation statements)

References 41 publications

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“…Thus, blocking reconsolidation of the CS-withdrawal memory through infusion of Zif268 ASO at memory reactivation abolishes the ability of the CS to suppress heroin seeking in the future. These data greatly extend our previous observations that intra-BLA Zif268 ASO disrupts the reconsolidation of appetitive drug-associated memories for drugpaired stimuli (Lee et al, 2005(Lee et al, , 2006, by showing that aversive drug memories are also susceptible to disruption in this manner. Although MSO-infused animals in the post-reactivation session were significantly more suppressed than in the prereactivation test, this is likely attributable to the 5 additional consecutive days of withdrawal conditioning (i.e., naloxone-CS pairings) these animals received after the initial test session.…”

Section: Discussionsupporting

confidence: 87%

“…In our study, animals that did not experience reactivation of the CS-withdrawal memory but were infused with Zif268 ASOs before testing showed the same degree of conditioned suppression of heroin seeking as that seen in the MSO-infused controls. Thus, our data confirm that the effects of Zif268 ASO on the impairment of appetitive and aversive memory reconsolidation are reactivation dependent (Lee et al, 2005(Lee et al, , 2006Debiec et al, 2006). Some studies have demonstrated a recovery from amnesia after reconsolidation blockade with repeated testing (Lattal and Abel, 2004;Power et al 2006), whereas others have found no evidence of recovery (Duvarci and Nader, 2004;Lee et al, 2004).…”

Section: Discussionsupporting

confidence: 85%

“…Studies from our laboratory have shown that appetitive drug memories undergo protein synthesis-dependent reconsolidation in the BLA. Intra-BLA infusions of antisense oligodeoxynucleotides (ASOs) targeting the immediate-early gene Zif268 before memory reactivation of a CS-cocaine or CS-fear association resulted in a significant reactivation-dependent reconsolidation deficit (Lee et al, 2005) and prevented cue-maintained cocaine seeking and cue-induced relapse (Lee et al, 2006). Expression of Zif268 is upregulated in the BLA after reexposure to CSs previously paired with both cocaine (Thomas et al, 2003) and footshock (Hall et al, 2001), and intra-BLA Zif268 ASO knocks down Zif268 protein in the BLA after reexposure to a CS paired with footshock (Lee et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Disrupting Reconsolidation of Conditioned Withdrawal Memories in the Basolateral Amygdala Reduces Suppression of Heroin Seeking in Rats

Hellemans¹,

Everitt²

2006

J. Neurosci.

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Recent data from our laboratory have demonstrated that appetitive drug memories undergo protein synthesis-dependent reconsolidation in the basolateral amygdala (BLA), an area important in the formation of emotional memories. We here investigated the importance of the BLA in the reconsolidation of opiate conditioned withdrawal memories. Rats with bilateral cannulas implanted in the BLA were trained to respond for heroin (0.12 mg/kg, i.v.) under a seeking-taking schedule, which required responding on a seeking lever to gain the opportunity to self-administer heroin by a single response on a taking lever. After induction of opiate dependence with subcutaneously implanted, heroin-filled osmotic minipumps (3 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 heroin), rats received five consecutive pairings of a conditioned stimulus (CS) (tone, light, and odor compound) paired with naloxone (0.10 mg/kg, s.c.)-precipitated withdrawal. We replicated our previous findings that heroin seeking is suppressed in the presence of the withdrawal-associated CS. However, infusion of Zif268 antisense oligodeoxynucleotide into the BLA before reactivation of the CS-withdrawal association abolished this conditioned suppression in a reactivation-dependent manner. We also report that reconsolidation of CS-withdrawal memories upregulates Zif268 protein in the basolateral but not central nucleus of the amygdala and that Zif268 knockdown occurs selectively in the BLA. These results demonstrate that drug withdrawal memories undergo protein synthesis-dependent reconsolidation in the BLA and suggest a common mechanism for the reconsolidation of both appetitive and aversive drug memories.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Disrupting Reconsolidation of Conditioned Withdrawal Memories in the Basolateral Amygdala Reduces Suppression of Heroin Seeking in Rats

Hellemans¹,

Everitt²

2006

J. Neurosci.

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“…More recently though, decreases in EGR1 mRNA expression have been documented during forced abstinence from highdose cocaine self-administration binges (Mutschler et al, 2000). The potential importance of EGR1 in cocaine-related behaviors has been demonstrated in antisense injection and mutant mouse experiments (Lee et al, 2005(Lee et al, , 2006Valjent et al, 2006). The finding of decreases in histone H3 acetylation at 1 and 10 days of abstinence suggests a decrease in active transcription of EGR1.…”

Section: Discussionmentioning

confidence: 99%

Persistent Alterations in Mesolimbic Gene Expression with Abstinence from Cocaine Self-Administration

Freeman

Patel

Brucklacher

et al. 2007

Neuropsychopharmacol

110

126

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Cocaine-responsive gene expression changes have been described after either no drug abstinence or short periods of abstinence. Little data exist on the persistence of these changes after long-term abstinence. Previously, we reported that after discrete-trial cocaine selfadministration and 10 days of forced abstinence, incubation of cocaine reinforcement was observable by a progressive ratio schedule. The present study used rat discrete-trial cocaine self-administration and long-term forced abstinence to examine extinction responding, mRNA abundance of known cocaine-responsive genes, and chromatin remodeling. At 30 and 100 days of abstinence, extinction responding increased compared to 3-day abstinent rats. Decreases in both medial prefrontal cortex (mPFC) and nucleus accumbens cfos, Nr4a1, Arc, and EGR1 mRNA were observed, and in most cases persisted, for 100 days of abstinence. The signaling peptides CART and neuropeptide Y (NPY) transiently increased in the mPFC, but returned to baseline levels following 10 days of abstinence. To investigate a potential regulatory mechanism for these persistent mRNA changes, levels of histone H3 acetylation at promoters for genes with altered mRNA expression were examined. In the mPFC, histone H3 acetylation decreased after 1 and 10 days of abstinence at the promoter for EGR1. H3 acetylation increased for NPY after 1 day of abstinence and returned to control levels by 10 days of abstinence.Behaviorally, these results demonstrate incubation after discrete-trial cocaine self-administration and prolonged forced abstinence. This incubation is accompanied by changes in gene expression that persist long after cessation of drug administration and may be regulated by chromatin remodeling.

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“…exclusively triggered by long recall sessions, we predicted the preservation of conditioned fear because rBDNF would constrain extinction. If both processes were initiated under conditions when extinction was impaired, no fear response would be measured at LTM1 or LTM2, as the original memory supporting the CR would not undergo ZIf268-dependent reconsolidation (Lee et al 2004(Lee et al , 2005. Thus, amnesia would ensue.…”

mentioning

confidence: 99%

The exclusive induction of extinction is gated by BDNF

Kirtley¹,

Thomas²

2010

Learn. Mem.

Self Cite

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We have previously reported that the reconsolidation and extinction of hippocampal-dependent contextual fear memory can be initiated by a single context conditioned stimulus (CS) presentation of either short or long duration, and that both processes require protein synthesis in this brain region. Furthermore, reconsolidation depends on Zif268 activity in this region. Here we show that by infusing a recombinant brain-derived neurotrophic factor (rBDNF) directly into the brain of rats, that high levels of mature BDNF in the hippocampus at retrieval constrain the extinction of the fear memory after prolonged memory recall. We also show after a short CS exposure that reconsolidation was impaired using antisense oligonucleotides targeting Zif268, and that, similarly, reductions in conditioned behavior were observed after prolonged CS presentation when extinction is constrained by high levels of BDNF. This is direct evidence that in the mammalian brain extinction proceeds exclusively after prolonged CS exposure. In addition, that BDNF activity in the hippocampus contributes to a molecular switch for the extinction of hippocampal-dependent memory.

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Disrupting Reconsolidation of Drug Memories Reduces Cocaine-Seeking Behavior

Cited by 366 publications

References 41 publications

Disrupting Reconsolidation of Conditioned Withdrawal Memories in the Basolateral Amygdala Reduces Suppression of Heroin Seeking in Rats

Disrupting Reconsolidation of Conditioned Withdrawal Memories in the Basolateral Amygdala Reduces Suppression of Heroin Seeking in Rats

Persistent Alterations in Mesolimbic Gene Expression with Abstinence from Cocaine Self-Administration

The exclusive induction of extinction is gated by BDNF

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