c‐Fos expression associated with reinstatement of cocaine‐seeking behavior by response‐contingent conditioned cues

Kufahl, Peter R.; Zavala, Arturo R.; Singh, Akanksha; Thiel, Kenneth J.; Dickey, Erin D.; Joyce, Jeffrey N.; Neisewander, Janet L.

doi:10.1002/syn.20666

Cited by 91 publications

(92 citation statements)

References 63 publications

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“…We therefore suggest that the novel stimuli may have activated similar reinforcement and motivation processes as those involved in conditioned reinforcement-seeking behavior. In support, the Fos expression resulting from novel cue reinforcement was highly similar to that found previously during CS + re-exposure (Kufahl et al, 2009;Neisewander et al, 2000). The latter study also used a no-lever control group and found similar activation, suggesting that our findings are not due to the act of operant responding, but instead likely reflect circuits that have a role in drug motivational processes invoked for expression of cocaine-seeking behavior (Fuchs et al, 2002(Fuchs et al, , 2004(Fuchs et al, , 2006Ito et al, 2004;Kalivas and McFarland, 2003;Kruzich and See, 2001b).…”

Section: Novelty Reinforcementsupporting

confidence: 88%

“…In response to cocaine or cocaine-paired cues, Fos is expressed in brain regions commonly associated with reward processing, memory, and drug abuse (Ciccocioppo et al, 2001;Hotsenpiller et al, 2002;Neisewander et al, 2000). More recently, we found that presentation of response-contingent cocaine-paired cues during reinstatement testing induced a widespread pattern of Fos expression throughout the brain, including several prefrontal cortical, limbic, and striatal subregions (Kufahl et al, 2009). Although the association between cue presentation and brain activation appears to rely on previous drug-stimulus pairings (Guo et al, 2008;Miller and Marshall, 2005), little attention has been given to the contribution of novelty on test day.…”

Section: Introductionmentioning

confidence: 90%

“…Both of these measures are thought to reflect incentive motivational effects of the cues acquired through classical conditioning (Stewart, 1983). Further evidence supporting the construct validity of the model are that neuroimaging studies in human addicts and examination of immediate early gene (IEG) expression in animals that reveal the same brain regions are activated by cocaine-paired cues (Childress et al, 1999;Garavan et al, 2000;Grant et al, 1996;Kufahl et al, 2009;Wang et al, 1999;Zavala et al, 2008). In addition, compounds found to decrease self-reports of craving in humans have been shown to attenuate cue-elicited drug-seeking behavior in animals (Fuchs et al, 1998;Yahyavi-FirouzAbadi and See, 2009), demonstrating predictive validity and overall utility of the cue reinstatement model.…”

Section: Introductionmentioning

confidence: 99%

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Novel Cues Reinstate Cocaine-Seeking Behavior and Induce Fos Protein Expression as Effectively as Conditioned Cues

Bastle

Kufahl

Turk

et al. 2012

Neuropsychopharmacol

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Cue reinstatement of extinguished cocaine-seeking behavior is a widely used model of cue-elicited craving in abstinent human addicts. This study examined Fos protein expression in response to cocaine cues or to novel cues as a control for activation produced by test novelty. Rats were trained to self-administer cocaine paired with either a light or a tone cue, or received yoked saline and cue presentations, and then underwent daily extinction training. They were then tested for reinstatement of extinguished cocaine-seeking behavior elicited by response-contingent presentations of either the cocaine-paired cue or a novel cue (that is, tone for those trained with a light or vice versa). Surprisingly, conditioned and novel cues both reinstated responding and increased Fos similarly in most brain regions. Exceptions included the anterior cingulate, which was sensitive to test cue modality in saline controls and the dorsomedial caudate-putamen, where Fos was correlated with responding in the novel, but not conditioned, cue groups. In subsequent experiments, we observed a similar pattern of reinstatement in rats trained and tested for sucrose-seeking behavior, whereas rats trained and tested with the cues only reinstated to a novel, and not a familiar, light or tone. The results suggest that novel cues reinstate responding to a similar extent as conditioned cues regardless of whether animals have a reinforcement history with cocaine or sucrose, and that both types of cues activate similar brain circuits. Several explanations as to why converging processes may drive drug and novel cue reinforcement and seeking behavior are discussed.

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Section: Novelty Reinforcementsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Novel Cues Reinstate Cocaine-Seeking Behavior and Induce Fos Protein Expression as Effectively as Conditioned Cues

Bastle

Kufahl

Turk

et al. 2012

Neuropsychopharmacol

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“…The NAc, under the influence of dopamine (DA) release from the ventral tegmentum and glutamatergic afferents from the PFC, amygdala, and hippocampus, integrates limbic information related to memory, drive, and motivation with the generation of goal-directed motor behaviors (23). This area is also activated by conditioned cues in rats undergoing a variety of extinction manipulations (24)(25)(26).…”

Section: Discussionmentioning

confidence: 99%

Dorsolateral caudate nucleus differentiates cocaine from natural reward-associated contextual cues

Liu

Chefer

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Chronic drug administration induces neuroplastic changes within brain circuits regulating cognitive control and/or emotions. Following repeated pairings between drug intake and environmental cues, increased sensitivity to or salience of these contextual cues provoke conscious or unconscious craving and enhance susceptibility to relapse. To explore brain circuits participating in such experienceinduced plasticity, we combined functional MRI with a preclinical drug vs. food self-administration (SA) withdrawal model. Specifically, two groups of rats were trained to associate odor cues with the availability of i.v. cocaine or oral sucrose, respectively. After 20 d of cocaine or sucrose SA followed by prolonged (30 d) forced abstinence, animals were presented with odor cues previously associated with or without (S+/S−) reinforcer (cocaine/sucrose) availability while undergoing functional MRI scans. ANOVA results demonstrate that a learning effect distinguishing S+ from S− was seen in the insula and nucleus accumbens, with the insula response reflecting the individual history of cocaine SA intake. A main effect of group, distinguishing cocaine from sucrose, was seen in the medial prefrontal cortex (infralimbic, prelimbic, and cingulate cortex) and dorsolateral striatum. Critically, only the dorsomedial striatum demonstrated a double dissociation between the two SA groups and learning (S+ vs. S−). These findings demonstrate altered cortico-limbic-striatal reward-related processing to learned, environment reward-associated contextual odor cues, which may serve as potential biomarkers for therapeutic interventions.context cues | neuroplasticity | drug addiction P reventing or reducing the incidence of relapse remains the major challenge for the treatment of addiction, as recidivism rates can range as high as 90%. Both preclinical (1) and human addiction studies (2) have demonstrated that following repeated pairings with drug administration, various contextual and environmental stimuli when subsequently presented alone can elicit drug-seeking and drug-taking behaviors. Further, dysregulation within specific brain circuits regulating cognitive control and/or emotional regulation (3) can amplify the perceived salience of environmental contexts and cues that provoke craving (4) and thereby enhance susceptibility to relapse (2). These observations speak to the important role of reward learning in addictive processes (5). As such, it is critical to better understand the neural mechanisms and circuitry underlying the retrieval of cue-induced memories as an important intermediary in developing more efficacious interventions to decrease recidivism.The amygdala, nucleus accumbens (NAc), and various prefrontal cortical regions respond to drug-associated cues in human cocaine addicts (6, 7). Supporting their critical roles in the neural circuitry of drug-seeking behavior, these regions have also been identified using preclinical reinstatement models (8, 9). For example, NAc neurons exhibit conditioned responses to drugassociated env...

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“…These findings obtained in NAcc shell MSNs are consistent with adaptations processing information necessary for contextual conditioning and do not argue against similar changes occurring in the NAcc core. Indeed, both changes in c-Fos expression (Kufahl et al, 2009) and in spine morphology (Gipson et al, 2013) have been reported in the NAcc core following the presentation of discrete drug-paired cues.…”

Section: Associative Conditioningmentioning

confidence: 99%

Drug-Paired Contextual Stimuli Increase Dendritic Spine Dynamics in Select Nucleus Accumbens Neurons

Singer

Bubula

et al. 2016

Neuropsychopharmacol

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Repeated exposure to amphetamine leads to both associative conditioning and nonassociative sensitization. Here we assessed the contribution of neuronal ensembles in the nucleus accumbens (NAcc) to these behaviors. Animals exposed to amphetamine IP or in the ventral tegmental area (VTA) showed a sensitized locomotor response when challenged with amphetamine weeks later. Both exposure routes also increased ΔFosB levels in the NAcc. Further characterization of these ΔFosB+ neurons, however, revealed that amphetamine had no effect on dendritic spine density or size, indicating that these neurons do not undergo changes in dendritic spine morphology that accompany the expression of nonassociative sensitization. Additional experiments determined how neurons in the NAcc contribute to the expression of associative conditioning. A discrimination learning procedure was used to expose rats to IP or VTA amphetamine either Paired or Unpaired with an open field. As expected, compared with Controls, Paired rats administered IP amphetamine subsequently showed a conditioned locomotor response when challenged with saline in the open field, an effect accompanied by an increase in c-Fos+ neurons in the medial NAcc. Further characterization of these c-Fos+ cells revealed that Paired rats showed an increase in the density of dendritic spines and the frequency of medium-sized spines in the NAcc. In contrast, Paired rats previously exposed to VTA amphetamine showed neither conditioned locomotion nor conditioned c-Fos+ expression. Together, these results suggest a role for c-Fos+ neurons in the medial NAcc and rapid changes in the morphology of their dendritic spines in the expression of conditioning evoked by amphetaminepaired contextual stimuli.

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c‐Fos expression associated with reinstatement of cocaine‐seeking behavior by response‐contingent conditioned cues

Cited by 91 publications

References 63 publications

Novel Cues Reinstate Cocaine-Seeking Behavior and Induce Fos Protein Expression as Effectively as Conditioned Cues

Novel Cues Reinstate Cocaine-Seeking Behavior and Induce Fos Protein Expression as Effectively as Conditioned Cues

Dorsolateral caudate nucleus differentiates cocaine from natural reward-associated contextual cues

Drug-Paired Contextual Stimuli Increase Dendritic Spine Dynamics in Select Nucleus Accumbens Neurons

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