Renewal of extinguished cocaine-seeking

School of Psychology, The University of New South Wales, Sydney, New South Wales, 2052, Australia.
Neuroscience (Impact Factor: 3.36). 03/2008; 151(3):659-70. DOI: 10.1016/j.neuroscience.2007.11.018
Source: PubMed


Rats were trained to self-administer cocaine in a distinctive context (context A). They were then extinguished in a second context (context B) prior to test for cocaine-seeking in the original training context, context A (group ABA), context B (group ABB) or no test (group AB0). Group ABA showed renewal of extinguished cocaine-seeking associated with c-Fos induction in basolateral amygdala, lateral hypothalamus, and infralimbic prefrontal cortex. Groups ABA and ABB showed test-associated c-Fos induction in prelimbic prefrontal cortex, nucleus accumbens (core, shell, rostral pole), striatum, lateral amygdala, perifornical hypothalamus, and ventral tegmental area. Double immunofluorescence revealed that renewal-associated c-Fos was expressed in orexin-negative lateral hypothalamic neurons whereas test-associated c-Fos was expressed in orexin-positive perifornical hypothalamic neurons. Retrograde tracing from lateral hypothalamus with cholera toxin revealed only sparse dual-labeled neurons in basolateral amygdala and infralimbic prefrontal cortex, suggesting that these regions contribute to renewal of cocaine-seeking independently of their projections to lateral hypothalamus. Retrograde tracing from the ventral tegmental area suggested that hypothalamic contributions to cocaine-seeking are likewise independent of projections to the midbrain. These results suggest that renewal of cocaine-seeking depends critically on basolateral amygdala, lateral hypothalamus, and infralimbic prefrontal cortex. Whereas basolateral amygdala and lateral hypothalamus contributions may be common to renewal of extinguished cocaine-, alcohol-, and sucrose-seeking, infralimbic prefrontal cortex contributions appear unique to renewal of cocaine-seeking and may reflect the habitual nature of relapse to cocaine.

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Available from: Adam S Hamlin, Oct 04, 2015
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    • "Immunohistochemical assays indicated that Fos expression is increased during cocaine or heroin self-administration throughout the corticostriatal circuitry, including medial prefrontal and orbitofrontal cortex, nucleus accumbens core and shell subregions, and the dorsal striatum (Ben-Shahar et al., 2004; Larson et al., 2010; Madsen et al., 2012; Martin- Garcia et al., 2014; Pich et al., 1997; Thiel et al., 2010; Zahm et al., 2010). Even when drug is not onboard, contextual cues and discrete cues previously paired with drug selfadministration activate many of the same prefrontal cortex and striatal areas during reinstatement of lever pressing (Bastle et al., 2012; Bossert et al., 2011; Cruz et al., 2014; Fanous et al., 2012; Fanous et al., 2013; Hamlin et al., 2008; Kufahl et al., 2009; Mahler and Aston-Jones, 2012; Neisewander et al., 2000; Shalev et al., 2003; Zavala et al., 2007; Zhou et al., 2013) or exposure to the paired context alone without lever responding (Doherty et al., 2013). Perhaps due to higher variability, in situ hybridization and quantitative PCR assays for c-fos mRNA identify activation of only a subset of these same brain areas (Celentano et al., 2009; Daunais et al., 1993; Daunais et al., 1995; Hearing et al., 2008a; Hearing et al., 2008b; Koya et al., 2006; Kuntz et al., 2008; Kuzmin and Johansson, 1999). "
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    ABSTRACT: Learned associations between drugs and environment play an important role in addiction and are thought to be encoded within specific patterns of sparsely distributed neurons called neuronal ensembles. This hypothesis is supported by correlational data from in vivo electrophysiology and cellular imaging studies in relapse models in rodents. In particular, cellular imaging with the immediate early gene c-fos and its protein product Fos has been used to identify sparsely distributed neurons that were strongly activated during conditioned drug behaviors such as drug self-administration and context- and cue-induced reinstatement of drug seeking. Here we review how Fos and the c-fos promoter have been employed to demonstrate causal roles for Fos-expressing neuronal ensembles in prefrontal cortex and nucleus accumbens in conditioned drug behaviors. This work has allowed identification of unique molecular and electrophysiological alterations within Fos-expressing neuronal ensembles that may contribute to the development and expression of learned associations in addiction.This article is part of a Special Issue entitled SI:Addiction circuits.
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    • "Finally, brain regions that were robustly activated during inhibition of cocaine seeking were also previously shown to be involved in triggering cocaine seeking. This was the case for the PL, NAc core, LH, and VTA (McFarland et al. 2003, 2004; Harris et al. 2005; Hamlin et al. 2008; Marchant et al. 2009). Regarding the PL, this apparent contradiction may be resolved by postulating that the PL has a more general function in controlling cocaine seeking than inhibition or excitation per se. "
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    ABSTRACT: People with cocaine addiction retain some degree of prefrontal cortex (PFC) inhibitory control of cocaine craving, a brain capacity that may underlie the efficacy of cognitive behavioral therapy for addiction. Similar findings were recently found in rats after extended access to and escalation of cocaine self-administration. Rats' inhibitory control of cocaine seeking was flexible, sufficiently strong to suppress cocaine-primed reinstatement and depended, at least in part, on neuronal activity within the prelimbic (PL) PFC. Here, we used a large-scale and high-resolution Fos mapping approach to identify, beyond the PL PFC, how top-down and/or bottom-up PFC-subcortical circuits are recruited during inhibition of cocaine seeking. Overall, we found that effective inhibitory control of cocaine seeking is associated with the coordinated recruitment of different top-down cortical-striatal circuits originating from different PFC territories, and of different bottom-up dopamine (DA) and serotonin (5-HT) midbrain subsystems that normally modulate activity in these circuits. This integrated brain response suggests that rats concomitantly engage and experience intricate cognitive and affective processes when they have to inhibit intense cocaine seeking. Thus, even after extended drug use, rats can be successfully trained to engage whole-brain inhibitory control mechanisms to suppress cocaine seeking.
    Cerebral Cortex 05/2014; 25(9). DOI:10.1093/cercor/bhu112 · 8.67 Impact Factor
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    • "Until recently, the degree to which it did had been unclear. Although ABA renewal had been routinely demonstrated with either food or drug reinforcers (e.g., Bossert et al., 2004; Chaudri et al., 2009; Crombag and Shaham, 2002; Hamlin et al., 2007, 2008; Nakajima et al., 2000; Welker and McAuley, 1978; Zironi et al., 2006), several reports had failed to demonstrate AAB renewal (see Bossert et al., 2004; Crombag and Shaham, 2002; Nakajima et al., 2000) and the evidence for ABC renewal was mixed (e.g., Zironi et al., 2006). The lack of evidence of AAB and ABC renewal left unanswered the crucial question of whether mere removal from the extinction context was sufficient to cause response recovery. "
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    ABSTRACT: The purpose of this article is to review recent research that has investigated the effects of context change on instrumental (operant) learning. The first part of the article discusses instrumental extinction, in which the strength of a reinforced instrumental behavior declines when reinforcers are withdrawn. The results suggest that extinction of either simple or discriminated operant behavior is relatively specific to the context in which it is learned: As in prior studies of Pavlovian extinction, ABA, ABC, and AAB renewal effects can all be observed. Further analysis supports the idea that the organism learns to refrain from making a specific response in a specific context, or in more formal terms, an inhibitory context-response association. The second part of the article then discusses research suggesting that the context also controls instrumental behavior before it is extinguished. Several experiments demonstrate that a context switch after either simple or discriminated operant training causes a decrement in the strength of the response. Over a range of conditions, the animal appears to learn a direct association between the context and the response. Under some conditions, it can also learn a hierarchical representation of context and the response-reinforcer relation. Extinction is still more context-specific than conditioning, as indicated by ABC and AAB renewal. Overall, the results establish that the context can play a significant role in both the acquisition and extinction of operant behavior.
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