Uncertainty exposure causes behavioural sensitization and increases risky decision-making in male rats: toward modelling gambling disorder

Zeeb, Fiona D.; Li, Zhaoxia; Fisher, Daniel C.; Zack, Martin; Fletcher, Paul

doi:10.1503/jpn.170003

Cited by 78 publications

(22 citation statements)

References 43 publications

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“…One potential explanation may be an increase in risk tolerance, as animals are repeatedly exposed to testing. Indeed, exposing animals to unpredictable schedules of reward increases risky decision making . However, animals have previously been shown to demonstrate consistent performance across multiple test days on the rGT, indicating that increased risk tolerance alone is insufficient to account for the increase in disadvantageous choice and rather exposure to cocaine appears to be critical in instantiating or exacerbating these negative effects.…”

Section: Discussionmentioning

confidence: 99%

Impaired decision making following escalation of cocaine self‐administration predicts vulnerability to relapse in rats

et al. 2019

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Impairments in cost-benefit decision making represent a cardinal feature of drug addiction. However, whether these alterations predate drug exposure, thereby contributing to facilitating loss of control over drug intake, or alternatively arise as a result of drug use and subsequently confer vulnerability to relapse has yet to be determined.Male Sprague-Dawley rats were trained to self-administer (SA) cocaine during 19 daily long-access (12-h) sessions; conditions reliably shown to promote escalation.One week after cocaine SA, rats underwent an extinction/relapse test immediately followed by conditioned stimuli-, stress-, and drug-primed reinstatement challenges.The influence of escalated cocaine intake on decision making was measured over time by four test sessions of a rodent analogue of the Iowa Gambling Task (rGT), once prior to cocaine exposure and then 1 day, 1 week, and 1 month after the last SA session. Substantial individual variability was observed in the influence of escalated cocaineSA on decision-making performance. A subset of rats displayed pronounced deficits, while others showed unaffected or even improved performance on the rat Gambling Task (rGT) 24 hours after the last SA session. When challenged with a relapse test after 1 week of forced abstinence, animals that showed impaired decision making following SA displayed an increased propensity to respond for cocaine under extinction.These data suggest that decision-making deficits in individuals with drug addiction are not antecedent to-but arise as a consequence of-drug exposure. Moreover, these data indicate that susceptibility to the deleterious effects of drugs on decision making confers vulnerability toward relapse.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Section: Discussionmentioning

confidence: 99%

Impaired decision making following escalation of cocaine self‐administration predicts vulnerability to relapse in rats

et al. 2019

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“…Crucially, it appears that repeated exposure to reward uncertainty subsequently increases risk preference on the rGT (Zeeb, Li, Fisher, Zack, & Fletcher, 2017). Similarly, the introduction of salient cues to winning trials, to what is termed the cued rGT, results in riskier and more disadvantageous choice behavior than when exposed to the uncued task (Barrus & Winstanley, 2016).…”

Section: Cue Sensitivity and Sensitization In Gamblingmentioning

confidence: 99%

“…Cross-sensitization and the resulting hyperresponsivity of dopaminergic systems also occurs between drugs of abuse and natural rewards (Avena & Hoebel, 2003) and drugs of abuse and stress (at both behavioral and physiological levels) (Cruz, Marin, Leão, & Planeta, 2011;Garcia-Keller et al, 2013;Piazza et al, 1990). There is also evidence for cross-sensitization between drugs of abuse and gambling (Boileau et al, 2014;Mascia et al, 2018;Singer, Scott-Railton, & Vezina, 2012;Zack, Featherstone, Mathewson, & Fletcher, 2014;Zeeb et al, 2017), and between gambling and stress (C. L. Green et al, 2017).…”

Section: Cross-sensitization: Definitionmentioning

confidence: 99%

“…Interestingly, in many of these patients, discontinuation of their dopaminergic medication resolved their pathological gambling (Dodd et al, 2005). There is also direct evidence for cross-sensitization of the dopaminergic system under gambling-like conditions in animals (Mascia et al, 2018;Singer et al, 2012;Zack et al, 2014;Zeeb et al, 2017). Uncertainty causes cross-sensitization of the dopaminergic system, as seen by increased reactivity to a single dose of amphetamine, in the same way that repeated exposure to drugs of abuse sensitizes this system.…”

Section: Addictionmentioning

confidence: 99%

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Cued for risk: Evidence for an incentive sensitization framework to explain the interplay between stress and anxiety, substance abuse, and reward uncertainty in disordered gambling behavior

Hellberg

Russell

Robinson

2018

Cogn Affect Behav Neurosci

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Gambling disorder is an impairing condition confounded by psychiatric co-morbidity, particularly with substance use and anxiety disorders. Yet, our knowledge of the mechanisms that cause these disorders to coalesce remains limited. The Incentive Sensitization Theory suggests that sensitization of neural Bwanting^pathways, which attribute incentive salience to rewards and their cues, is responsible for the excessive desire for drugs and cue-triggered craving. The resulting hyper-reactivity of the Bwanting' system is believed to heavily influence compulsive drug use and relapse. Notably, evidence for sensitization of the mesolimbic dopamine pathway has been seen across gambling and substance use, as well as anxiety and stress-related pathology, with stress playing a major role in relapse. Together, this evidence highlights a phenomenon known as cross-sensitization, whereby sensitization to stress, drugs, or gambling behaviors enhance the sensitivity and dopaminergic response to any of those stimuli. Here, we review the literature on how cue attraction and reward uncertainty may underlie gambling pathology, and examine how this framework may advance our understanding of co-mordidity with substance-use disorders (e.g., alcohol, nicotine) and anxiety disorders. We argue that reward uncertainty, as seen in slot machines and games of chance, increases dopaminergic activity in the mesolimbic pathway and enhances the incentive value of reward cues. We propose that incentive sensitization by reward uncertainty may interact with and predispose individuals to drug abuse and stress, creating a mechanism through which co-mordidity of these disorders may emerge.

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“…A priming dose of amphetamine can increase motivation to gamble [21] and pathological gamblers show evidence for greater amphetamineinduced striatal DA release [22], suggesting that the two disorders share overlapping mechanisms and are susceptible to crosssensitization [23,24]. Some recent preclinical studies have directly supported this possibility, but are limited to demonstrations that exposure to uncertainty enhances the locomotor response to amphetamine [25][26][27].…”

Section: Introductionmentioning

confidence: 99%

Exposure to conditions of uncertainty promotes the pursuit of amphetamine

Mascia

Neugebauer

Brown

et al. 2018

Neuropsychopharmacol

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Prior exposure to abused drugs leads to long-lasting neuroadaptations culminating in excessive drug intake. Given the comorbidity between substance use and gambling disorders, surprisingly little is known about the effects of exposure to reinforcement contingencies experienced during games of chance. As it is a central feature of these games, we characterized the effects of exposure to uncertainty on biochemical and behavioral effects normally observed in rats exposed to amphetamine. Rats in different groups were trained to nose-poke for saccharin under certain [fixed-ratio (FR)] or uncertain conditions [variable-ratio (VR)] for 55 1-h sessions. Ratios were escalated on successive sessions and rats maintained on the last ratio (FR/VR 20) for 20-25 days. Two to three weeks later, rats were tested for their locomotor or nucleus accumbens dopamine (NAcc DA) response to amphetamine or self-administration of the drug using a lever press operant. NAcc DA overflow was also assessed in additional rats during the saccharin sessions. Rats exposed to uncertainty subsequently showed a higher locomotor and NAcc DA response to amphetamine and self-administered more drug infusions relative to rats exposed to predictable reinforcement. NAcc DA levels during the saccharin sessions tracked the variance of the scheduled ratios (a measure of uncertainty). VR rats showed escalating DA overflow with increasing ratios. Exposure to uncertainty triggered neuroadaptations similar to those produced by exposure to abused drugs. As these were produced in drug naive rats both during and after exposure to uncertainty, they provide a novel common pathway to drug and behavioral addictions.

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Uncertainty exposure causes behavioural sensitization and increases risky decision-making in male rats: toward modelling gambling disorder

Cited by 78 publications

References 43 publications

Impaired decision making following escalation of cocaine self‐administration predicts vulnerability to relapse in rats

Impaired decision making following escalation of cocaine self‐administration predicts vulnerability to relapse in rats

Cued for risk: Evidence for an incentive sensitization framework to explain the interplay between stress and anxiety, substance abuse, and reward uncertainty in disordered gambling behavior

Exposure to conditions of uncertainty promotes the pursuit of amphetamine

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