Abnormal associative encoding in orbitofrontal neurons in cocaine‐experienced rats during decision‐making

Department of Psychiatry, University of Maryland, Baltimore, Baltimore, Maryland, United States
European Journal of Neuroscience (Impact Factor: 3.18). 12/2006; 24(9):2643-53. DOI: 10.1111/j.1460-9568.2006.05128.x
Source: PubMed


Recent evidence has linked exposure to addictive drugs to an inability to employ information about adverse consequences, or outcomes, to control behavior. For instance, addicts and drug-experienced animals fail to adapt their behavior to avoid adverse outcomes in gambling and reversal tasks or after changes in the value of expected rewards. These deficits are similar to those caused by damage to the orbitofrontal cortex, suggesting that addictive drugs may cause long-lasting changes in the representation of outcome associations in a circuit that includes the orbitofrontal cortex. Here we test this hypothesis by recording from orbitofrontal neurons in a discrimination task in rats previously exposed to cocaine (30 mg/kg i.p. for 14 days). We found that orbitofrontal neurons recorded in cocaine-experienced rats failed to signal the adverse outcome at the time a decision was made in the task. The loss of this signal was associated with abnormal changes in response latencies on aversive trials. Furthermore, upon reversal of the cue-outcome associations, orbitofrontal neurons in cocaine-treated rats with enduring reversal impairments failed to reverse their cue-selectivity, while orbitofrontal neurons in cocaine-treated rats with normal performance showed an increase in the plasticity of cue-selective firing after reversal. These results provide direct neurophysiological evidence that exposure to cocaine can cause behaviorally relevant changes in the processing of associative information in a circuit that includes the orbitofrontal cortex.

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Available from: Geoffrey Schoenbaum, Feb 03, 2014
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    • "Disruption of frontostriatal interactions in cocaine-dependent individuals may be at the core of the behavioral manifestations of addiction, such as compulsive drug seeking and impaired self-control. Indeed, studies in animals have shown that cocaine exposure causes an inability of the OFC to signal adverse outcomes (Stalnaker et al. 2006), which in association with enhanced dorso-striatal activity leads to rigid patterns of behavior (Caprioli, Lucantonio & Schoenbaum 2014). Thus, the 'hard wired' nature of the observed neural changes could explain the notorious difficulties experienced by addicts to abandon drug use even in the face of serious health and social consequences and the high relapse rate observed in this population. "
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    ABSTRACT: Cocaine addiction has been associated with increased sensitivity of the human reward circuit to drug-related stimuli. However, the capacity of non-drug incentives to engage this network is poorly understood. Here, we characterized the functional sensitivity to monetary incentives and the structural integrity of the human reward circuit in abstinent cocaine-dependent (CD) patients and their matched controls. We assessed the BOLD response to monetary gains and losses in 30 CD patients and 30 healthy controls performing a lottery task in a magnetic resonance imaging scanner. We measured brain gray matter volume (GMV) using voxel-based morphometry and white matter microstructure using voxel-based fractional anisotropy (FA). Functional data showed that, after monetary incentives, CD patients exhibited higher activation in the ventral striatum than controls. Furthermore, we observed an inverted BOLD response pattern in the prefrontal cortex, with activity being highest after unexpected high gains and lowest after losses. Patients showed increased GMV in the caudate and the orbitofrontal cortex, increased white matter FA in the orbito-striatal pathway but decreased FA in antero-posterior association bundles. Abnormal activation in the prefrontal cortex correlated with GMV and FA increases in the orbitofrontal cortex. While functional abnormalities in the ventral striatum were inversely correlated with abstinence duration, structural alterations were not. In conclusion, results suggest abnormal incentive processing in CD patients with high salience for rewards and punishments in subcortical structures but diminished prefrontal control after adverse outcomes. They further suggest that hypertrophy and hyper-connectivity within the reward circuit, to the expense of connectivity outside this network, characterize cocaine addiction.
    Full-text · Article · Jan 2016 · Addiction Biology
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    • "Thus, the only reasonable explanation that accounts for the current results is alterations in model-based processing. While this does not preclude a contribution of stronger habits to other aspects of drug seeking, it is in fact consistent with what we and others have reported, which is that psychostimulants cause rather modest changes in information processing in dorsal striatum (Takahashi et al. 2007) while substantially altering that in orbitofrontal cortex (Homayoun and Moghaddam 2006; Stalnaker et al. 2006). So, what are the implications of these findings for understanding and, more importantly, addressing behavioral issues in addiction? "
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    ABSTRACT: Addiction is characterized by maladaptive decision-making, in which individuals seem unable to use adverse outcomes to modify their behavior. Adverse outcomes are often infrequent, delayed, and even rare events, especially when compared to the reliable rewarding drug-associated outcomes. As a result, recognizing and using information about their occurrence put a premium on the operation of so-called model-based systems of behavioral control, which allow one to mentally simulate outcomes of different courses of action based on knowledge of the underlying associative structure of the environment. This suggests that addiction may reflect, in part, drug-induced dysfunction in these systems. Here, we tested this hypothesis. This study aimed to test whether cocaine causes deficits in model-based behavior and learning independent of requirements for response inhibition or perception of costs or punishment. We trained rats to self-administer sucrose or cocaine for 2 weeks. Four weeks later, the rats began training on a sensory preconditioning and inferred value blocking task. Like devaluation, normal performance on this task requires representations of the underlying task structure; however, unlike devaluation, it does not require either response inhibition or adapting behavior to reflect aversive outcomes. Rats trained to self-administer cocaine failed to show conditioned responding or blocking to the preconditioned cue. These deficits were not observed in sucrose-trained rats nor did they reflect any changes in responding to cues paired directly with reward. These results imply that cocaine disrupts the operation of neural circuits that mediate model-based behavioral control.
    Full-text · Article · Aug 2013 · Psychopharmacology
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    • "Rats having self-administered and then been withdrawn from cocaine exhibited both increased extinction responding and a marked deficit in reversal learning during withdrawal (Calu et al., 2007). Schoenbaum and colleagues have emphasized both the similarity between OFC lesions and these apparently long-lasting effects of relatively short-term treatment with cocaine, but also showed that the deficit in reversal learning is reflected in a change in the properties of OFC neurons, which do not develop appropriate responses to cues predicting outcomes (Stalnaker et al., 2006). Other considerations implicate the orbitofrontal cortex in compulsivity related to chronic drug abuse. "
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    ABSTRACT: We revisit our hypothesis that drug addiction can be viewed as the endpoint of a series of transitions from initial voluntarily drug use to habitual, and ultimately compulsive drug use. We especially focus on the transitions in striatal control over drug seeking behaviour that underlie these transitions since functional heterogeneity of the striatum was a key area of Ann Kelley's research interests and one in which she made enormous contributions. We also discuss the hypothesis in light of recent data that the emergence of a compulsive drug seeking habit both reflects a shift to dorsal striatal control over behaviour and impaired prefontal cortical inhibitory control mechanisms. We further discuss aspects of the vulnerability to compulsive drug use and in particular the impact of impulsivity. In writing this review we acknowledge the untimely death of an outstanding scientist and a dear personal friend.
    Full-text · Article · Feb 2013 · Neuroscience & Biobehavioral Reviews
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