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• W2007653857 abstract "Maladaptive memories that associate environmental stimuli with the effects of drugs of abuse are known to be a major cause of relapse to, and persistence of, a drug addictive habit. However, memories may be disrupted after their acquisition and consolidation by impairing their reconsolidation. Here, we show that infusion of Zif268 antisense oligodeoxynucleotides into the basolateral amygdala, prior to the reactivation of a well-learned memory for a conditioned stimulus (CS)-cocaine association, abolishes the acquired conditioned reinforcing properties of the drug-associated stimulus and thus its impact on the learning of a new cocaine-seeking response. Furthermore, we show that reconsolidation of CS-fear memories also requires Zif268 in the amygdala. These results demonstrate that appetitive CS-drug memories undergo reconsolidation in a manner similar to aversive memories and that this amygdala-dependent reconsolidation can be disrupted to reduce the impact of drug cues on drug seeking. Maladaptive memories that associate environmental stimuli with the effects of drugs of abuse are known to be a major cause of relapse to, and persistence of, a drug addictive habit. However, memories may be disrupted after their acquisition and consolidation by impairing their reconsolidation. Here, we show that infusion of Zif268 antisense oligodeoxynucleotides into the basolateral amygdala, prior to the reactivation of a well-learned memory for a conditioned stimulus (CS)-cocaine association, abolishes the acquired conditioned reinforcing properties of the drug-associated stimulus and thus its impact on the learning of a new cocaine-seeking response. Furthermore, we show that reconsolidation of CS-fear memories also requires Zif268 in the amygdala. These results demonstrate that appetitive CS-drug memories undergo reconsolidation in a manner similar to aversive memories and that this amygdala-dependent reconsolidation can be disrupted to reduce the impact of drug cues on drug seeking. Drug cues are known to induce craving and relapse in abstinent humans (Childress et al., 1999Childress A.R. Mozley P.D. McElgin W. Fitzgerald J. Reivich M. O’Brien C.P. Limbic activation during cue-induced cocaine craving.Am. J. Psychiatry. 1999; 156: 11-18PubMed Google Scholar, Ehrman et al., 1992Ehrman R.N. Robbins S.J. Childress A.R. O’Brien C.P. Conditioned-responses to cocaine-related stimuli in cocaine abuse patients.Psychopharmacology (Berl.). 1992; 107: 523-529Crossref PubMed Scopus (362) Google Scholar, Gawin, 1991Gawin F.H. Cocaine addiction—psychology and neurophysiology.Science. 1991; 251: 1580-1586Crossref PubMed Scopus (635) Google Scholar, O’Brien et al., 1998O’Brien C.P. Childress A.R. Ehrman R. Robbins S.J. Conditioning factors in drug abuse: can they explain compulsion?.J. Psychopharmacol. 1998; 12: 15-22Crossref PubMed Scopus (523) Google Scholar), as well as relapse to drug seeking in experimental animals (de Wit and Stewart, 1981de Wit H. Stewart J. Reinstatement of cocaine-reinforced responding in the rat.Psychopharmacology (Berl.). 1981; 75: 134-143Crossref PubMed Scopus (740) Google Scholar, Fuchs et al., 1998Fuchs R.A. Tran-Nguyen L.T.L. Specio S.E. Groff R.S. Neisewander J.L. Predictive validity of the extinction/reinstatement model of drug craving.Psychopharmacology (Berl.). 1998; 135: 151-160Crossref PubMed Scopus (104) Google Scholar, Meil and See, 1996Meil W.M. See R.E. Conditioned cued recovery of responding following prolonged withdrawal from self-administered cocaine in rats: An animal model of relapse.Behav. Pharmacol. 1996; 7: 754-763PubMed Google Scholar, Weiss et al., 2000Weiss F. Maldonado-Vlaar C.S. Parsons L.H. Kerr T.M. Smith D.L. Ben-Shahar O. Control of cocaine-seeking behavior by drug-associated stimuli in rats: Effects on recovery of extinguished operant-responding and extracellular dopamine levels in amygdala and nucleus accumbens.Proc. Natl. Acad. Sci. USA. 2000; 97: 4321-4326Crossref PubMed Scopus (341) Google Scholar), and attempts to extinguish their powerful acquired properties have not generally been successful as a treatment strategy for drug addiction (Conklin and Tiffany, 2002Conklin C.A. Tiffany S.T. Applying extinction research and theory to cue-exposure addiction treatments.Addiction. 2002; 97: 155-167Crossref PubMed Scopus (504) Google Scholar, Di Ciano and Everitt, 2004Di Ciano P. Everitt B.J. Conditioned reinforcing properties of stimuli paired with self-administered cocaine, heroin or sucrose: implications for the persistence of addictive behaviour.Neuropharmacology. 2004; 47: 202-213Crossref PubMed Scopus (139) Google Scholar). Several experimental models of drug addiction have shown that the formation of a conditioned stimulus (CS)-drug association during drug self-administration training enables that CS subsequently to induce and maintain drug seeking for prolonged periods (Arroyo et al., 1998Arroyo M. Markou A. Robbins T.W. Everitt B.J. Acquisition, maintenance and reinstatement of intravenous cocaine self-administration under a second-order schedule of reinforcement in rats: effects of conditioned cues and continuous access to cocaine.Psychopharmacology (Berl.). 1998; 140: 331-344Crossref PubMed Scopus (214) Google Scholar, Goldberg, 1975Goldberg S.R. Stimuli associated with drug injections as events that control behavior.Pharmacol. Rev. 1975; 27: 325-340PubMed Google Scholar), to retard the extinction of drug seeking (Ciccocioppo et al., 2004Ciccocioppo R. Martin-Fardon R. Weiss F. Stimuli associated with a single cocaine experience elicit long-lasting cocaine-seeking.Nat. Neurosci. 2004; 7: 495-496Crossref PubMed Scopus (87) Google Scholar, Ranaldi and Roberts, 1996Ranaldi R. Roberts D.C.S. Initiation, maintenance and extinction of cocaine self-administration with and without conditioned reward.Psychopharmacology (Berl.). 1996; 128: 89-96Crossref PubMed Scopus (50) Google Scholar), and to induce relapse to drug seeking in extinguished or abstinent animals (de Wit and Stewart, 1981de Wit H. Stewart J. Reinstatement of cocaine-reinforced responding in the rat.Psychopharmacology (Berl.). 1981; 75: 134-143Crossref PubMed Scopus (740) Google Scholar, Fuchs et al., 1998Fuchs R.A. Tran-Nguyen L.T.L. Specio S.E. Groff R.S. Neisewander J.L. Predictive validity of the extinction/reinstatement model of drug craving.Psychopharmacology (Berl.). 1998; 135: 151-160Crossref PubMed Scopus (104) Google Scholar, Grimm et al., 2001Grimm J.W. Hope B.T. Wise R.A. Shaham Y. Neuroadaptation. Incubation of cocaine craving after withdrawal.Nature. 2001; 412: 141-142Crossref PubMed Scopus (677) Google Scholar, Meil and See, 1996Meil W.M. See R.E. Conditioned cued recovery of responding following prolonged withdrawal from self-administered cocaine in rats: An animal model of relapse.Behav. Pharmacol. 1996; 7: 754-763PubMed Google Scholar). Through predictive association with the drug’s effects, the CS acquires powerful and enduring conditioned reinforcing properties (Di Ciano and Everitt, 2004Di Ciano P. Everitt B.J. Conditioned reinforcing properties of stimuli paired with self-administered cocaine, heroin or sucrose: implications for the persistence of addictive behaviour.Neuropharmacology. 2004; 47: 202-213Crossref PubMed Scopus (139) Google Scholar, Grimm et al., 2001Grimm J.W. Hope B.T. Wise R.A. Shaham Y. Neuroadaptation. Incubation of cocaine craving after withdrawal.Nature. 2001; 412: 141-142Crossref PubMed Scopus (677) Google Scholar), thereby enabling it to support prolonged periods of drug-seeking behavior (Arroyo et al., 1998Arroyo M. Markou A. Robbins T.W. Everitt B.J. Acquisition, maintenance and reinstatement of intravenous cocaine self-administration under a second-order schedule of reinforcement in rats: effects of conditioned cues and continuous access to cocaine.Psychopharmacology (Berl.). 1998; 140: 331-344Crossref PubMed Scopus (214) Google Scholar) and the learning of new drug-seeking responses (Di Ciano and Everitt, 2004Di Ciano P. Everitt B.J. Conditioned reinforcing properties of stimuli paired with self-administered cocaine, heroin or sucrose: implications for the persistence of addictive behaviour.Neuropharmacology. 2004; 47: 202-213Crossref PubMed Scopus (139) Google Scholar). Indeed, a specific test of the conditioned reinforcing properties of a CS is its ability to support new instrumental learning (Mackintosh, 1974Mackintosh N.J. The Psychology of Animal Learning. Academic Press, London1974Google Scholar), and so an acquisition of new response with conditioned reinforcement procedure can be used to assess the impact that drug cues will have on drug seeking. Indeed, this procedure models directly one important aspect of human addictive behavior, namely the rapid acquisition of novel, flexible drug-seeking strategies (Di Ciano and Everitt, 2004Di Ciano P. Everitt B.J. Conditioned reinforcing properties of stimuli paired with self-administered cocaine, heroin or sucrose: implications for the persistence of addictive behaviour.Neuropharmacology. 2004; 47: 202-213Crossref PubMed Scopus (139) Google Scholar). Therapeutically, there is great interest in reducing the impact that drug cues have on addictive behavior and relapse, and to prevent them from reinforcing new drug-seeking actions that lead to the compulsive drug-seeking characteristic of the addicted state (DSM-IV-TR, 2000DSM-IV-TRDiagnostic and Statistical Manual of Mental Disorders.Fourth Edition, Text Revision. American Psychiatric Association Press, Washington, DC2000Google Scholar). Though extinction of the CS-drug association has not proved to be effective in reducing drug seeking or relapse in either humans (Conklin and Tiffany, 2002Conklin C.A. Tiffany S.T. Applying extinction research and theory to cue-exposure addiction treatments.Addiction. 2002; 97: 155-167Crossref PubMed Scopus (504) Google Scholar) or rats (Di Ciano and Everitt, 2004Di Ciano P. Everitt B.J. Conditioned reinforcing properties of stimuli paired with self-administered cocaine, heroin or sucrose: implications for the persistence of addictive behaviour.Neuropharmacology. 2004; 47: 202-213Crossref PubMed Scopus (139) Google Scholar), the behavioral impact of a CS may be greatly reduced by preventing the reconsolidation of the previously learned memories that are retrieved and reactivated by its presentation (Nader et al., 2000Nader K. Schafe G.E. Le Doux J.E. Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval.Nature. 2000; 406: 722-726Crossref PubMed Scopus (1822) Google Scholar). Reconsolidation impairments, characterized by amnesia that is critically dependent upon memory reactivation through CS exposure, have been observed in several forms of memory (Alberini, 2005Alberini C.M. Mechanisms of memory stabilization: are consolidation and reconsolidation similar or distinct processes?.Trends Neurosci. 2005; 28: 51-56Abstract Full Text Full Text PDF PubMed Scopus (464) Google Scholar, Dudai and Eisenberg, 2004Dudai Y. Eisenberg M. Rites of passage of the engram: reconsolidation and the lingering consolidation hypothesis.Neuron. 2004; 44: 93-100Abstract Full Text Full Text PDF PubMed Scopus (344) Google Scholar). Importantly, reconsolidation of amygdala-dependent conditioned fear has been disrupted by intraamygdala infusion of the protein synthesis inhibitor anisomycin (Nader et al., 2000Nader K. Schafe G.E. Le Doux J.E. Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval.Nature. 2000; 406: 722-726Crossref PubMed Scopus (1822) Google Scholar). The basolateral amygdala (BLA) is an important locus of CS-US associations in both aversive and appetitive learning (Everitt et al., 2000Everitt B.J. Cardinal R.N. Hall J. Parkinson J.A. Robbins T.W. Differential involvement of amygdala subsystems in appetitive conditioning and drug addiction.in: Aggleton J.P. The Amygdala: A Functional Analysis. Oxford University Press, Oxford2000: 353-390Google Scholar, LeDoux, 2000LeDoux J.E. Emotion circuits in the brain.Annu. Rev. Neurosci. 2000; 23: 155-184Crossref PubMed Scopus (5778) Google Scholar), and BLA lesions impair the ability of drug-associated CSs to acquire drug seeking under a second-order schedule of reinforcement (Whitelaw et al., 1996Whitelaw R.B. Markou A. Robbins T.W. Everitt B.J. Excitotoxic lesions of the basolateral amygdala impair the acquisition of cocaine-seeking behaviour under a second-order schedule of reinforcement.Psychopharmacology (Berl.). 1996; 127: 213-224Crossref PubMed Google Scholar), and to induce reinstatement of drug seeking following extinction in rats (Meil and See, 1997Meil W.M. See R.E. Lesions of the basolateral amygdala abolish the ability of drug associated cues to reinstate responding during withdrawal from self-administered cocaine.Behav. Brain Res. 1997; 87: 139-148Crossref PubMed Scopus (276) Google Scholar). The hypothesis that we tested here was that drug memories undergo BLA-dependent reconsolidation and that preventing this process would reduce the impact that drug cues have on drug seeking and relapse. A protein that may be necessary for the reconsolidation of amygdala-dependent CS-US associations is the product of the immediate-early gene Zif268 (also known as EGR1, NGFI-A, and Krox24), since its expression is significantly upregulated in the BLA following reexposure to discrete CSs previously associated with either footshock (Hall et al., 2001Hall J. Thomas K.L. Everitt B.J. Cellular imaging of zif268 expression in the hippocampus and amygdala during contextual and cued fear memory retrieval: Selective activation of hippocampal CA1 neurons during the recall of contextual memories.J. Neurosci. 2001; 21: 2186-2193Crossref PubMed Google Scholar) or self-administered cocaine (Thomas et al., 2003Thomas K.L. Arroyo M. Everitt B.J. Induction of the learning and plasticity-associated gene Zif268 following exposure to a discrete cocaine-associated stimulus.Eur. J. Neurosci. 2003; 17: 1964-1972Crossref PubMed Scopus (88) Google Scholar). Similar cellular imaging data demonstrated that hippocampal Zif268 expression was also highly correlated with the recall of context-shock, and not CS-shock, associations (Hall et al., 2001Hall J. Thomas K.L. Everitt B.J. Cellular imaging of zif268 expression in the hippocampus and amygdala during contextual and cued fear memory retrieval: Selective activation of hippocampal CA1 neurons during the recall of contextual memories.J. Neurosci. 2001; 21: 2186-2193Crossref PubMed Google Scholar), and the knockdown of Zif268 protein in the hippocampus, through intracranial infusion of Zif268 antisense oligodeoxynucleotides (ASO), was subsequently shown to disrupt the reconsolidation of contextual fear memories (Lee et al., 2004Lee J.L.C. Everitt B.J. Thomas K.L. Independent cellular processes for hippocampal memory consolidation and reconsolidation.Science. 2004; 304: 839-843Crossref PubMed Scopus (621) Google Scholar). Therefore, we investigated whether the drug cue-induced upregulation of Zif268 in the amygdala was functionally required for the reconsolidation of memories elicited by discrete appetitive, drug-associated as well as aversive CSs. Reconsolidation of the CS-drug association was assessed by testing the ability of the drug-associated CS to support the learning of a new instrumental drug-seeking response, since this depends specifically on its conditioned reinforcing properties (Di Ciano and Everitt, 2004Di Ciano P. Everitt B.J. Conditioned reinforcing properties of stimuli paired with self-administered cocaine, heroin or sucrose: implications for the persistence of addictive behaviour.Neuropharmacology. 2004; 47: 202-213Crossref PubMed Scopus (139) Google Scholar). We also tested the requirement for Zif268 in the amygdala in the reconsolidation of CS-shock associations in a conditioned freezing procedure (Hall et al., 2001Hall J. Thomas K.L. Everitt B.J. Cellular imaging of zif268 expression in the hippocampus and amygdala during contextual and cued fear memory retrieval: Selective activation of hippocampal CA1 neurons during the recall of contextual memories.J. Neurosci. 2001; 21: 2186-2193Crossref PubMed Google Scholar, Nader et al., 2000Nader K. Schafe G.E. Le Doux J.E. Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval.Nature. 2000; 406: 722-726Crossref PubMed Scopus (1822) Google Scholar). The acquisition of a new response with conditioned reinforcement procedure used here is similar to that previously described (Di Ciano and Everitt, 2004Di Ciano P. Everitt B.J. Conditioned reinforcing properties of stimuli paired with self-administered cocaine, heroin or sucrose: implications for the persistence of addictive behaviour.Neuropharmacology. 2004; 47: 202-213Crossref PubMed Scopus (139) Google Scholar). Rats were implanted with an intravenous (i.v.) catheter, and with chronic indwelling guide cannulae positioned bilaterally in the BLA (Figure 1). Following recovery from surgery, all rats underwent 9 days of cocaine self-administration training (nosepoke responding), during which each self-administered cocaine infusion was paired with a 20 s light CS. The conditioned reinforcing properties of the CS were tested subsequently by measuring its ability to support the acquisition of the new instrumental drug-seeking response of lever pressing in the absence of the primary drug reinforcer (Di Ciano and Everitt, 2004Di Ciano P. Everitt B.J. Conditioned reinforcing properties of stimuli paired with self-administered cocaine, heroin or sucrose: implications for the persistence of addictive behaviour.Neuropharmacology. 2004; 47: 202-213Crossref PubMed Scopus (139) Google Scholar). Between the training and test stages, the rats were exposed to a brief 15 min session in which a nosepoke resulted in presentation of the CS, but an infusion of saline instead of cocaine. Pilot studies confirmed that this session was sufficient to reactivate the previously formed CS-drug association and render it sensitive to disruption. Thus, the infusion of anisomycin (62.5 μg/0.5 μl/side) into the BLA immediately after reactivation subsequently impaired the acquisition of the new response (Figure S1 in the Supplemental Data available with this article online), thereby demonstrating a reduction in the conditioned reinforcing properties of the drug-associated stimulus. In the present experiment, either Zif268 ASO or scrambled missense oligodeoxynucleotides (MSO) was infused 90 min prior to the reactivation session (established by our earlier work [Lee et al., 2004Lee J.L.C. Everitt B.J. Thomas K.L. Independent cellular processes for hippocampal memory consolidation and reconsolidation.Science. 2004; 304: 839-843Crossref PubMed Scopus (621) Google Scholar]), or at the same time after training with the reactivation session omitted. The infused Zif268 ASO/MSO spread throughout the BLA as well as diffusing into the central nucleus of the amygdala (CeN; Figures 1D and 1E), but not into the surrounding cortices or overlying caudate putamen, and was cleared within 24 hr of infusion (Figure 1F). Zif268 ASO infusion into the BLA resulted in a marked, reactivation-dependent impairment in the acquisition of the new instrumental drug-seeking response. The reactivated control MSO group learned to respond on the active lever for the CS over the four sessions of acquisition (1, 2, 5, and 8 days after reactivation), and responding was significantly higher than on the inactive lever (Figure 2A ). In contrast, the reactivated Zif268 ASO-infused group made many fewer responses on the active lever than control rats and showed no preference for the active lever over the inactive lever for up to 8 days after reactivation. The ASO-induced impairment in the acquisition of a new response was critically dependent upon reactivation of the CS-drug memory, since rats that were infused with Zif268 ASO, but with the memory reactivation session omitted, readily learned the new instrumental response with conditioned reinforcement. Both Zif268 ASO- and MSO-infused rats in the nonreactivated condition thus showed strong preference for the active lever over the inactive lever (Figure 2B). An overall comparison of reactivated and nonreactivated groups revealed a reactivation-dependent effect of ASO infusion upon lever preference at the third and fourth test sessions, which indicates a persistent failure to learn the new response. Indeed, repeated testing of a subgroup of Zif268 ASO-infused rats revealed a complete failure to learn the new instrumental response up to 27 days after reactivation (Figure 2C). Given that reactivation dependence is an important criterion for the reconsolidation process (Lewis, 1979Lewis D.J. Psychobiology of active and inactive memory.Psychol. Bull. 1979; 86: 1054-1083Crossref PubMed Scopus (365) Google Scholar), the present results demonstrate that CS-drug associations undergo reconsolidation and that Zif268 ASO infusion into the BLA impairs this reconsolidation process. Importantly, there was no difference between the groups in overall (inactive and active) lever-pressing activity or nosepoke responses during the test sessions (Figure S2), which reveals that there was no deficit in general motivation or activity. Furthermore, the reactivation dependence of the impairment demonstrates that Zif268 ASO had no nonspecific effects on lever-pressing performance. Prior to the conditioned reinforcement test, all groups acquired to the same degree the nosepoke response under a fixed-ratio 1 (FR1) schedule for i.v. cocaine reinforcement (data not shown; all ps > 0.28), and the total number of CS-drug pairings was similar across all groups (data not shown; ASO × reactivation; F < 1). Importantly, therefore, conditioning of the CS-drug association was equivalent in all groups. Finally, during the reactivation session the ASO and MSO groups performed similar numbers of nosepoke responses (Figure 2D) and consequently received similar numbers of nonreinforced CS exposures (Figure 2E). Therefore, the ASO-induced impairment in the acquisition of a new response cannot be attributed to prior differences in conditioning, CS exposure or extinction. Following completion of the acquisition of a new response testing, and in order to establish whether aversive as well as appetitive CS memories are dependent upon Zif268 in the amygdala, the same animals were fear conditioned to an auditory CS (see Experimental Procedures). On the following day, the rats were again infused into the BLA with Zif268 ASO or MSO (rats were allocated to experimental groups at random and independently from the acquisition of a new response study), 90 min prior to a brief presentation of the CS to reactivate the CS-footshock association (and to test long-term memory [LTM] for the association). While there was no effect of the ASO infusions on freezing 3 hr after reactivation (i.e., postreactivation short-term memory [PR-STM] was unaffected), ASO infusion resulted in a severe reactivation-dependent impairment in conditioned freezing to the CS both 24 hr (postreactivation long-term memory [PR-LTM]) and 7 days (PR-LTM2) after reactivation (Figure 3A ). Rats that were infused with Zif268 ASO, but not reactivated, were not impaired at any test (Figure 3B). The stable reconsolidation deficit, with intact STM but impaired LTM after reactivation, was not related to any difference in conditioning (freezing at the initial LTM test was the same). In order to demonstrate that Zif268 ASO infusion does indeed reduce Zif268 protein levels in the BLA, we fear-conditioned six rats and infused them with Zif268 ASO or MSO 90 min prior to fear memory reactivation (LTM test). The rats were then killed, and the BLA was microdissected, 2 hr after reactivation, a time point at which we have shown previously that Zif268 protein is elevated (Lee et al., 2004Lee J.L.C. Everitt B.J. Thomas K.L. Independent cellular processes for hippocampal memory consolidation and reconsolidation.Science. 2004; 304: 839-843Crossref PubMed Scopus (621) Google Scholar). Western blot analysis of BLA Zif268 protein levels (Lee et al., 2004Lee J.L.C. Everitt B.J. Thomas K.L. Independent cellular processes for hippocampal memory consolidation and reconsolidation.Science. 2004; 304: 839-843Crossref PubMed Scopus (621) Google Scholar) revealed a 65% reduction in ASO-infused rats, relative to MSO-infused controls (Figure 3C). Therefore intra-BLA Zif268 ASO infusion knocks down Zif268 protein in the BLA, consistent with previous results using the same ASO sequence (Malkani et al., 2004Malkani S. Wallace K.J. Donley M.P. Rosen J.B. An egr-1 (zif268) antisense oligodeoxynucleotide infused into the amygdala disrupts fear conditioning.Learn. Mem. 2004; 11: 617-624Crossref PubMed Scopus (96) Google Scholar). The present results demonstrate that addictive drug memories undergo reconsolidation in a manner similar to fear memories. Specifically, we have demonstrated amnesia for a well-trained and fully consolidated appetitively conditioned CS-drug association. A single reactivation-dependent infusion of Zif268 ASO into the amygdala, 24 hr prior to the first test of new learning, resulted in a long-lasting disruption of the ability of a drug-associated stimulus to act as a conditioned reinforcer and support the learning of a new instrumental seeking response. Therefore, the amnesia was both reactivation dependent and stable, two properties that are of critical importance in the definition of reconsolidation impairments (Dudai, 2004Dudai Y. The neurobiology of consolidations, or, how stable is the engram?.Annu. Rev. Psychol. 2004; 55: 51-86Crossref PubMed Scopus (1136) Google Scholar, Lewis, 1979Lewis D.J. Psychobiology of active and inactive memory.Psychol. Bull. 1979; 86: 1054-1083Crossref PubMed Scopus (365) Google Scholar). There were no neurotoxic effects of ASO infusions in the amygdala and no nonspecific behavioral effects of Zif268 ASO infusion. The amnesia could be attributed neither to differences in the conditioning of the CS-drug association during self-administration training, nor to different levels of extinction or memory reactivation through CS reexposure. Moreover, the same intraamygdala Zif268 ASO infusion also blocked the reconsolidation of CS-fear memories. The acquisition of a new response procedure used here tests specifically the conditioned reinforcing properties of a drug-associated CS (Di Ciano and Everitt, 2004Di Ciano P. Everitt B.J. Conditioned reinforcing properties of stimuli paired with self-administered cocaine, heroin or sucrose: implications for the persistence of addictive behaviour.Neuropharmacology. 2004; 47: 202-213Crossref PubMed Scopus (139) Google Scholar, Mackintosh, 1974Mackintosh N.J. The Psychology of Animal Learning. Academic Press, London1974Google Scholar). Indeed, explicit pairing of the CS with cocaine during self-administration has been shown to be an absolute requirement for its subsequent ability to support the acquisition of a new instrumental response (Di Ciano and Everitt, 2004Di Ciano P. Everitt B.J. Conditioned reinforcing properties of stimuli paired with self-administered cocaine, heroin or sucrose: implications for the persistence of addictive behaviour.Neuropharmacology. 2004; 47: 202-213Crossref PubMed Scopus (139) Google Scholar), confirming that it is the acquired conditioned reinforcing properties of the CS that support learning. As drug-associated conditioned reinforcers are known to induce craving in humans and relapse in humans and animals (Childress et al., 1999Childress A.R. Mozley P.D. McElgin W. Fitzgerald J. Reivich M. O’Brien C.P. Limbic activation during cue-induced cocaine craving.Am. J. Psychiatry. 1999; 156: 11-18PubMed Google Scholar, de Wit and Stewart, 1981de Wit H. Stewart J. Reinstatement of cocaine-reinforced responding in the rat.Psychopharmacology (Berl.). 1981; 75: 134-143Crossref PubMed Scopus (740) Google Scholar, Ehrman et al., 1992Ehrman R.N. Robbins S.J. Childress A.R. O’Brien C.P. Conditioned-responses to cocaine-related stimuli in cocaine abuse patients.Psychopharmacology (Berl.). 1992; 107: 523-529Crossref PubMed Scopus (362) Google Scholar, Fuchs et al., 1998Fuchs R.A. Tran-Nguyen L.T.L. Specio S.E. Groff R.S. Neisewander J.L. Predictive validity of the extinction/reinstatement model of drug craving.Psychopharmacology (Berl.). 1998; 135: 151-160Crossref PubMed Scopus (104) Google Scholar, Gawin, 1991Gawin F.H. Cocaine addiction—psychology and neurophysiology.Science. 1991; 251: 1580-1586Crossref PubMed Scopus (635) Google Scholar, Meil and See, 1996Meil W.M. See R.E. Conditioned cued recovery of responding following prolonged withdrawal from self-administered cocaine in rats: An animal model of relapse.Behav. Pharmacol. 1996; 7: 754-763PubMed Google Scholar, O’Brien et al., 1998O’Brien C.P. Childress A.R. Ehrman R. Robbins S.J. Conditioning factors in drug abuse: can they explain compulsion?.J. Psychopharmacol. 1998; 12: 15-22Crossref PubMed Scopus (523) Google Scholar, Weiss et al., 2000Weiss F. Maldonado-Vlaar C.S. Parsons L.H. Kerr T.M. Smith D.L. Ben-Shahar O. Control of cocaine-seeking behavior by drug-associated stimuli in rats: Effects on recovery of extinguished operant-responding and extracellular dopamine levels in amygdala and nucleus accumbens.Proc. Natl. Acad. Sci. USA. 2000; 97: 4321-4326Crossref PubMed Scopus (341) Google Scholar), the acquisition of a new response with conditioned reinforcement procedure provides an optimal method with which to assess the impact that drug cues will have on relapse to drug seeking. The instrumental response acquired with conditioned reinforcement models the learning of flexible drug-seeking strategies that typify addictive behavior in humans. It has been shown previously to be persistent despite the absence of further pairings of the CS with drug" @default.
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• W2007653857 title "Disrupting Reconsolidation of Drug Memories Reduces Cocaine-Seeking Behavior" @default.
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• W2007653857 doi "https://doi.org/10.1016/j.neuron.2005.08.007" @default.
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