Most rats prefer gambling opportunities featuring win-paired cues that drive risky choice: Synergistic interactions between choice of and choice during the cued rat gambling task

Although poor decision-making is a hallmark of psychiatric conditions such as attention deficit/hyperactivity disorder, pathological gambling or substance abuse, a fraction of healthy individuals exhibit similar poor decision-making performances in everyday life and specific laboratory tasks such as the Iowa Gambling Task. These particular individuals may provide information on risk factors or common endophenotypes of these mental disorders. In a rodent version of the Iowa gambling task – the Rat Gambling Task (RGT), we identified a population of poor decision makers, and assessed how these rats scored for several behavioral traits relevant to executive disorders: risk taking, reward seeking, behavioral inflexibility, and several aspects of impulsivity. First, we found that poor decision-making could not be well predicted by single behavioral and cognitive characteristics when considered separately. By contrast, a combination of independent traits in the same individual, namely risk taking, reward seeking, behavioral inflexibility, as well as motor impulsivity, was highly predictive of poor decision-making. Second, using a reinforcement-learning model of the RGT, we confirmed that only the combination of extreme scores on these traits could induce maladaptive decision-making. Third, the model suggested that a combination of these behavioral traits results in an inaccurate representation of rewards and penalties and inefficient learning of the environment. Poor decision-making appears as a consequence of the over-valuation of high-reward-high-risk options in the task. Such a specific psychological profile could greatly impair clinically healthy individuals in decision-making tasks and may predispose to mental disorders with similar symptoms.

Gambling disorder is a growing societal concern, as recognized by its recent classification as an addictive disorder in the DSM-5. Case reports have shown that disulfiram reduces gambling-related behavior in humans. The purpose of the present study was to determine whether disulfiram affects performance on a rat gambling task, a rodent version of the Iowa gambling task in humans, and whether any changes were associated with alterations in dopamine and/or norepinephrine levels. Rats were administered disulfiram prior to testing on the rat gambling task or prior to analysis of dopamine or norepinephrine levels in brain homogenates. Rats in the behavioral task were divided into two subgroups (optimal vs suboptimal) based on their baseline levels of performance in the rat gambling task. Rats in the optimal group chose the advantageous strategy more, and rats in the suboptimal group (a parallel to problem gambling) chose the disadvantageous strategy more. Rats were not divided into optimal or suboptimal groups prior to neurochemical analysis. Disulfiram administered 2h, but not 30min, before the task dose-dependently improved choice behavior in the rats with an initial disadvantageous "gambling-like" strategy, while having no effect on the rats employing an advantageous strategy. The behavioral effects of disulfiram were associated with increased striatal dopamine and decreased striatal norepinephrine. These findings suggest that combined actions on dopamine and norepinephrine may be a useful treatment for gambling disorders.

Rats trained to perform a version of the rat gambling task (rGT) in which salient audiovisual cues accompany reward delivery, similar to commercial gambling products, show greater preference for risky options. Given previous demonstrations that probabilistic reinforcement schedules can enhance psychostimulant-induced increases in accumbal DA and locomotor activity, we theorized that performing this cued task could perpetuate a proaddiction phenotype. Significantly more rats developed a preference for the risky options in the cued versus uncued rGT at baseline, and this bias was further exacerbated by cocaine self-administration, whereas the choice pattern of optimal decision-makers was unaffected. The addition of reward-paired cues therefore increased the proportion of rats exhibiting a maladaptive cognitive response to cocaine self-administration. Risky choice was not associated with responding for conditioned reinforcement or a marker of goal/sign-tracking, suggesting that reward-concurrent cues precipitate maladaptive choice via a unique mechanism unrelated to simple approach toward, or responding for, conditioned stimuli. Although "protected" from any resulting decision-making impairment, optimal decision-makers trained on the cued rGT nevertheless self-administered more cocaine than those trained on the uncued task. Collectively, these data suggest that repeated engagement with heavily cued probabilistic reward schedules can drive addiction vulnerability through multiple behavioral mechanisms. Rats trained on the cued rGT also exhibited blunted locomotor sensitization and lower basal accumbal DA levels, yet greater cocaine-induced increases in accumbal DA efflux. Gambling in the presence of salient cues may therefore result in an adaptive downregulation of the mesolimbic DA system, rendering individuals more sensitive to the deleterious effects of taking cocaine.SIGNIFICANCE STATEMENT Impaired cost/benefit decision making, exemplified by preference for the risky, disadvantageous options on the Iowa Gambling Task, is associated with greater risk of relapse and treatment failure in substance use disorder. Understanding factors that enhance preference for risk may help elucidate the neurobiological mechanisms underlying maladaptive decision making in addiction, thereby improving treatment outcomes. Problem gambling is also highly comorbid with substance use disorder, and many commercial gambling products incorporate salient win-paired cues. Here we show that adding reward-concurrent cues to a rat analog of the IGT precipitates a hypodopaminergic state, characterized by blunted accumbal DA efflux and attenuated locomotor sensitization, which may contribute to the enhanced responsivity to uncertain rewards or the reinforcing effects of cocaine we observed.

Pathological gambling (PG) is characterized by persistent, maladaptive gambling behavior, which disrupts personal and professional life. Animal models of gambling behavior could make a significant contribution to improving our understanding of the neural and neurochemical basis of gambling, and the treatment of PG. When gambling, failing to win critically results in the loss of resources wagered as well as the absence of additional gain. Here, we have incorporated these concepts into a novel rat gambling task (rGT), based, in part, on the 'Iowa' gambling task (IGT) commonly used clinically to measure gambling-like behavior. Rats choose among four different options to earn as many sugar pellets as possible within 30 min. Each option is associated with the delivery of a different amount of reward, but also with a different probability and duration of punishing time-out periods during which reward cannot be earned. The schedules are designed such that persistent choice of options linked with larger rewards result in fewer pellets earned per unit time. Rats learn to avoid these risky options to maximize their earnings, comparable with the optimal strategy in the IGT. Both d-amphetamine and the 5-HT(1A) receptor agonist, 8-OH-DPAT, impaired task performance. In contrast, the dopamine D(2) receptor antagonist, eticlopride, improved performance, whereas the D(1) receptor antagonist, SCH23390, had no effect. These data suggest that both serotonergic and dopaminergic agents can impair and improve gambling performance, and indicate that the rGT will be a useful tool to study the biological basis of gambling.

Decision-making requires individuals to perceive probabilities and risks associated with different options. The Iowa gambling task (IGT) is a widely used instrument that assesses decision-making under uncertainty and risk by varying monetary reinforcer/loss contingencies. The rat gambling task (rGT), based on the IGT, is a preclinical test using varying number of palatable reinforcers as wins and different duration of timeouts as punishment, mimicking losses. The rGT requires extensive operant training prior to the free choice sessions. The aim of the present study was to investigate if task acquisition and number of training days affected subsequent individual differences in decision-making strategies in the rGT, and if behavioral profiles impacted on task learning. Training time and performance of 70 male Lister Hooded rats from previously published studies were herein used to investigate whether learning time affected later decision-making strategies in the free choice rGT. Behavioral profiles generated from a subset of animals were used to study the impact of underlying behavior on learning time. There were differences in training days between fast, intermediate and slow learners. However, time required to acquire the rGT did not affect subsequent decision-making strategies in the free choice rGT. Finally, learning time was independent of underlying behavioral profiles. In conclusion, neither decision-making strategies in the rGT nor behavioral profiles were correlated or differed between animals with different learning speed. This suggests that the large variation in training time between animals is unrelated to subsequent decision-making strategies during free choice rGT. Such information is valuable for researchers using the rGT.

Social experiences during youth are thought to be critical for proper social and cognitive development. Conversely, social insults during development can cause long-lasting behavioral impairments and increase the vulnerability for psychopathology later in life. To investigate the importance of social experience during the juvenile and early adolescent stage for the development of cognitive control capacities, rats were socially isolated from postnatal day 21 to 42 followed by re-socialization until they reached adulthood. Subsequently, two behavioral dimensions of impulsivity (impulsive action in the five-choice serial reaction time task (5-CSRTT) and impulsive choice in the delayed reward task) and decision making (in the rat gambling task) were assessed. In a separate group of animals, long-lasting cellular and synaptic changes in adult medial prefrontal cortex (PFC) pyramidal neurons were determined following social isolation. Juvenile and early adolescent social isolation resulted in impairments in impulsive action and decision making under novel or challenging circumstances. Moreover, socially isolated rats had a reduced response to enhancement of dopaminergic neurotransmission (using amphetamine or GBR12909) in the 5-CSRTT under challenging conditions. Impulsive choice was not affected by social isolation. These behavioral deficits were accompanied by a loss of sensitivity to dopamine of pyramidal neurons in the medial PFC. Our data show long-lasting deleterious effects of early social isolation on cognitive control and its neural substrates. Alterations in prefrontal cognitive control mechanisms may contribute to the enhanced risk for psychiatric disorders induced by aberrations in the early social environment.

The use of illicit opioids has arguably never been more risky; street drug potency can be dangerously high, is often unknown to the consumer, and results in multiple daily fatalities worldwide. Furthermore, substance use disorder (SUD) is associated with increased maladaptive, risky decisions in laboratory-based gambling tasks. Animal studies can help determine whether this decision-making deficit is a cause or consequence of drug use. However, most experiments have only assessed psychostimulant drugs. To assess differences in decision-making strategies both before, during, and after self-administration of fentanyl in male and female Long Evans rats. Male and female Long Evans rats were trained to perform the rat gambling task (rGT), loosely based on the Iowa Gambling Task (IGT) used clinically, and/or self-administer fentanyl. We used the cued version of the rGT, in which sound and light stimuli signal sugar pellet rewards, as cocaine self-administration has the greatest effects on decision making in this task variant. After training on the cued rGT, female rats self-administered fentanyl more readily, an effect that was most apparent in optimal decision-makers. Contrary to previous reports using cocaine self-administration, decision-making was unaffected during fentanyl self-administration training in either sex. However, risky decision-making increased throughout forced abstinence from fentanyl in males. These findings complement those from human subjects, in whom preference for uncertain outcomes increased before relapse. These data highlight an abstinence-induced change in cognition that is unique to opiates as compared to psychostimulants, and which may critically contribute to the maintenance of addiction and relapse.

Poor decision-making is a core problem in psychiatric disorders such as pathological gambling and substance abuse. Both trait and environmental factors are considerably important to affect decision-making. However, it has not yet been systematically shown how they interact to affect risk preference in animal models evaluating decision-making. Here, we trained rats, housed in pairs or in isolation, in a touch screen chamber to detect the association between four different light signals on the screen and accompanied reward and punishment outcomes arranged with different schedules. Then, the rats were allowed to freely choose from 4 different light signals. Once animals showed a stabilized pattern of preference (risk-averse or risk-seeking), they were injected with saline or cocaine (a single injection per day for 7 days) followed by 2 weeks of withdrawal. Then, their preference of choice was re-tested in the touch screen chamber while they were cocaine challenged. All rats significantly changed their preference toward more risky choices when they were exposed to and challenged with cocaine, except those in the risk-averse/isolated housing group. These results indicate that the pre-existing trait toward risk and the housing condition interact to affect the quality of decision-making, and cocaine may help to aggravate this process.

Win-Paired Cues Modulate the Effect of Dopamine Neuron Sensitization on Decision Making and Cocaine Self-administration: Divergent Effects Across Sex

Risky decision-making is characteristic of depression and of addictive disorders, including pathological gambling. However it is not clear whether a propensity to risky choices predisposes to depressive symptoms or whether the converse is the case. Here we tested the hypothesis that rats showing risky decision-making in a rat gambling task (rGT) would be more prone to depressive-like behaviour in the learned helplessness (LH) model. Results showed that baseline rGT choice behaviour did not predict escape deficits in the LH protocol. In contrast, exposure to the LH protocol resulted in a significant increase in risky rGT choices on retest. Unexpectedly, control rats subjected only to escapable stress in the LH protocol showed a subsequent decrease in riskier rGT choices. Further analyses indicated that the LH protocol affected primarily rats with high baseline levels of risky choices and that among these it had opposite effects in rats exposed to LH-inducing stress compared to rats exposed only to the escape trials. Together these findings suggest that while baseline risky decision making may not predict LH behaviour it interacts strongly with LH conditions in modulating subsequent decision-making behaviour. The suggested possibility that stress controllability may be a key factor should be further investigated.

It is estimated that 0.6–1% of the population in the USA and Canada fulfil the Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-5) criteria for gambling disorders (GD). To date, there are no approved pharmacological treatments for GD. The rat gambling task (rGT) is a recently developed rodent analogue of the Iowa gambling task in which rats are trained to associate four response holes with different magnitudes and probabilities of food pellet rewards and punishing time-out periods. Similar to healthy human volunteers, most rats adopt the optimal strategies (optimal group). However, a subset of animals show preference for the disadvantageous options (suboptimal group), mimicking the choice pattern of patients with GD. Here, we explored for the first time the effects of various cannabinoid ligands (WIN 55,212-2, AM 4113, AM 630 and URB 597) on the rGT. Administration of the cannabinoid agonist CB1/CB2 WIN 55,212-2 improved choice strategy and increased choice latency in the suboptimal group, but only increased perseverative behaviour, when punished, in the optimal group. Blockade of CB1 or CB2 receptors or inhibition of fatty-acid amide hydrolase did not affect rGT performance. These results suggest that stimulation of cannabinoid receptors could affect gambling choice behaviours differentially in some subgroups of subjects.

Proper measurement of expected risk is important for making rational decisions, and maladaptive decision making may underlie various psychiatric disorders. However, differentially expressed genetic profiling involved in this process is still largely unknown. A rodent version of the gambling task (rGT) has been developed to measure decision-making by adopting the same principle of Iowa Gambling Task in humans. In the present study, we examined using next-generation sequencing (NGS) technique whether there are differences in gene expression profiles in the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAc) when rats make different choices toward risk in rGT. Rats were trained in a touch screen chamber to learn the relationships between 4 different light signals on the window of the screen and accompanied reward outcomes or punishments set up with different magnitudes and probabilities. Once they showed a stabilized pattern of preference upon free choice, rats were classified into risk-averse or risk-seeking groups. After performing the rGT, rats were decapitated, the mPFC and the NAc was dissected out, and NGS was performed with the total RNA extracted. We found that 477 and 36 genes were differentially expressed (approximately 75 and 83% out of them were downregulated) in the mPFC and the NAc, respectively, in risk-seeking compared to risk-averse rats. Among those, we suggested a few top ranked genes that may contribute to promoting risky choices. Our findings provide insights into transcriptional components underlying risky choices in rats.

Dopaminergic transmission within the ventral striatum is broadly implicated in risk/reward decision making and impulse control, and the rat gambling task (rGT) measures both behaviours concurrently. While the resulting indices of risky choice and impulsivity correlate at the population level, dopaminergic manipulations rarely impact both behaviours uniformly, with changes in choice more likely when dopaminergic transmission is altered during task acquisition. Although the task structure of the rGT remains constant, the relative importance of ventral striatal dopamine signals relevant for reward prediction versus impulse control may vary as learning progresses; the former should dominate while rats learn the probabilistic contingencies of the task, whereas suppression of premature responses becomes more valuable once a decision-making strategy is established and exploited. Striatal cholinergic interneurons (CINs) critically influence reinforcement learning by modulating dopamine release and gating periods of dopamine-facilitated neuroplasticity. We therefore hypothesised that ventral striatal CINs (vsCINs) could influence reward learning or impulse control during task acquisition or stable performance, respectively. Using chemogenetics in Sprague Dawley rats (Rattus norvegicus), we found support for this hypothesis: activation and inhibition of vsCINs once behaviour was stable increased and decreased motor impulsivity in both sexes but had no effect on choice patterns. In contrast, activating and inhibiting vsCINs during task acquisition did not alter motor impulsivity but instead decreased and increased risky choice, respectively. Notably, the former effect was only observed in males, and the latter in females. We conclude by proposing testable predictions regarding acetylcholine-dopamine interactions that may explain sex differences.Significance Statement Impairments in decision making and impulsivity are central to psychiatric conditions such as addiction, ADHD, and impulse control disorders. Understanding how these behaviours are regulated in the brain, and why they differ across individuals and sexes, is critical for developing targeted treatments. This study identifies ventral striatal cholinergic interneurons as important modulators of both impulsivity and risk-based decision making, with their influence depending on learning stage and biological sex. These results show how acetylcholine and dopamine systems interact to shape behaviour in flexible and individualized ways. By revealing circuit-level mechanisms that may underlie sex-specific vulnerabilities and stage-specific treatment outcomes, this work lays the groundwork for more personalized approaches to treating disorders involving poor impulse control and risky decision making.

Dopaminergic transmission within the nucleus accumbens is broadly implicated in risk/reward decision making and impulse control, and the rat gambling task (rGT) measures both behaviours concurrently. While the resulting indices of risky choice and impulsivity correlate at the population level, dopaminergic manipulations rarely impact both behaviours uniformly, with changes in choice more likely when dopaminergic transmission is altered during task acquisition. Although the task structure of the rGT remains constant, the importance of accumbal dopamine signals relevant for reward prediction versus impulse control may vary over time; the former should dominate while learning which option maximises sugar pellet profits, while the suppression of premature responses becomes more valuable once a decision-making strategy is set and can be exploited. Cholinergic interneurons (CINs) critically control dopamine release within the striatum, and can also encode latent task states deciphered by the frontal cortex. We theorised that aCINs may set the dopaminergic tone of the accumbens to maximise reward learning or impulse control during task acquisition or performance, respectively. Using chemogenetics, we found some support for this hypothesis: activation and inhibition of aCINs once behaviour was stable increased and decreased motor impulsivity in both sexes but had no effect on choice patterns. In contrast, activating and inhibiting aCINs throughout task acquisition did not alter motor impulsivity, but decreased and increased risky choice respectively. However, the former effect was only seen in males and the latter in females. We conclude by proposing a set of testable predictions regarding interactions between acetylcholine and dopamine that could explain these sex differences.

Decision-making requires that individuals perceive the probabilities and risks associated with different options. Experimental human and animal laboratory testing provide complimentary insights on the psychobiological underpinnings of decision-making. The Iowa gambling task (IGT) is a widely used instrument that assesses decision-making under uncertainty and risk. In the task participants are faced with a choice conflict between cards with varying monetary reinforcer/loss contingencies. The rat gambling task (rGT) is a pre-clinical version using palatable reinforcers as wins and timeouts mimicking losses. However, interspecies studies elaborating on human and rat behavior in these tasks are lacking. This study explores decision-making strategies among young adults (N = 270) performing a computerized version of the IGT, and adult outbred male Lister Hooded rats (N = 72) performing the rGT. Both group and individual data were explored by normative scoring approaches and subgroup formations based on individual choices were investigated. Overall results showed that most humans and rats learned to favor the advantageous choices, but to a widely different extent. Human performance was characterized by both exploration and learning as the task progressed, while rats showed relatively consistent pronounced preferences for the advantageous choices throughout the task. Nevertheless, humans and rats showed similar variability in individual choice preferences during end performance. Procedural differences impacting on the performance in both tasks and their potential to study different aspects of decision-making are discussed. This is a first attempt to increase the understanding of similarities and differences regarding decision-making processes in the IGT and rGT from an explorative perspective.