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Impulse control and/or gambling disorders can be triggered by dopamine agonist therapies used to treat Parkinson's disease, but the cognitive and neurobiological mechanisms underlying these adverse effects are unknown. Recent data show that adding win-paired sound and light cues to the rat gambling task (rGT) potentiates risky decision-making and impulsivity via the dopamine system, and that changing dopaminergic tone has a greater influence on behavior while subjects are learning task contingencies. Dopamine agonist therapy may therefore be potentiating risk-taking by amplifying the behavioral impact of gambling-related cues on novel behavior. Here, we show that ropinirole treatment in male rats transiently increased motor impulsivity but robustly and progressively increased choice of the high-risk/high-reward options when administered during acquisition of the cued but not uncued rGT. Early in training, ropinirole increased win-stay behavior after large unlikely wins on the cued rGT, indicative of enhanced model-free learning, which mediated the drug's effect on later risk preference.Ex vivocFos imaging showed that both chronic ropinirole and the addition of win-paired cues suppressed the activity of dopaminergic midbrain neurons. The ratio of midbrain:prefrontal cFos+neurons was lower in animals with suboptimal choice patterns and tended to predict risk preference across all rats. Network analyses further suggested that ropinirole induced decoupling of the dopaminergic cells of the VTA and nucleus accumbens but only when win-paired cues were present. Frontostriatal activity uninformed by the endogenous dopaminergic teaching signal therefore appeared to perpetuate risky choice, and ropinirole exaggerated this disconnect in synergy with reward-paired cues.SIGNIFICANCE STATEMENTD2/3receptor agonists, used to treat Parkinson's disease, can cause gambling disorder through an unknown mechanism. Ropinirole increased risky decision-making in rats, but only when wins were paired with casino-inspired sounds and lights. This was mediated by increased win-stay behavior after large unlikely wins early in learning, indicating enhanced model-free learning. cFos imaging showed that ropinirole suppressed activity of midbrain dopamine neurons, an effect that was mimicked by the addition of win-paired cues. The degree of risky choice rats exhibited was uniquely predicted by the ratio of midbrain dopamine:PFC activity. Depriving the PFC of the endogenous dopaminergic teaching signal may therefore drive risky decision-making on-task, and ropinirole acts synergistically with win-paired cues to amplify this.

Psychostimulant use and engagement with probabilistic schedules of reward both sensitize the mesocorticolimbic dopamine system. Such behaviours may act synergistically to explain the high comorbidity between stimulant use and gambling disorder. The salient audiovisual stimuli of modern electronic gambling may exacerbate the situation. To probe these interactions, we sensitized ventral tegmental area (VTA) dopamine neurons via chronic chemogenetic stimulation while rats learned the rat gambling task in the presence or absence of casino-like cues. The same rats then learned to self-administer cocaine. In a separate cohort, we confirmed that our chemogenetic methods sensitized the locomotor response to cocaine, and potentiated phasic excitability of VTA dopamine neurons through in vivo electrophysiological recordings. In the absence of cues, sensitization promoted risk-taking in both sexes. When rewards were cued, sensitization expedited the development of a risk-preferring phenotype in males, while attenuating cue-induced risk-taking in females. While these results provide further confirmation that VTA dopamine neurons critically modulate risky decision making, they also reveal stark sex differences in the decisional impact which dopaminergic signals exert when winning outcomes are cued. As previously observed, risky decision-making on the cued rGT increased as both males and females learned to self-administer cocaine. The combination of dopamine sensitization and win-paired cues while gambling lead to significantly greater cocaine-taking, but these rats did not show any increase in risky choice as a result. Cocaine and heavily-cued gambles may therefore partially substitute for each other once the dopamine system is rendered labile through sensitization, compounding addiction risk across modalities.

The main psychoactive compound within the cannabis plant, Δ9-tetrahydrocannabinol (THC), is thought to drive both the sensation of "high" and the cognitive impairments associated with cannabis consumption. Researchers keen to understand how cannabis impairs cognition have, therefore, studied the behavioral effects of systemic injections of THC in animal models. However, cannabis contains multiple other cannabinoids which may critically modulate the resulting cognitive effects. Users also typically eat or smoke cannabis, leading to concern over the translational validity of pure THC injections. We, therefore, tested whether acute oral administration of two different commercially available cannabis extracts, marketed as

Signalling reward delivery with sounds and lights is common practice in electronic games, and may seem like a superficially harmless feature of game design. Such audiovisual cues have been a defining feature of electronic gambling machines (EGMs) for decades and could contribute to their addictive potential. Indeed, adding casino-like cues to experimental gambling tasks enhances risk-taking in rats and humans. Cues are also important in driving drug use and relapse, as supported by the incentive sensitization theory. Given the critical relevance of cues in multiple addictive disorders, understanding the neural mechanism through which cues drive risk-taking could inform the use of pharmacotherapies. Behavioral pharmacology experiments in rats indicate that the functional regulation of decision making by dopamine, serotonin, noradrenaline and acetylcholine are all dramatically altered by the addition of reward-concurrent cues.

Risky or maladaptive decision making is thought to be central to the etiology of both drug and gambling addiction. Win-concurrent cues can enhance disadvantageous, risky choice in both rats and humans, yet it is unclear which aspects of the cue-reward contingencies drive this effect. Here, we implemented six variants of the rat Gambling Task (rGT), in which animals can maximise their sugar pellet profits by avoiding options paired with higher per-trial gains but disproportionately longer and more frequent time-out penalties. When audiovisual cues were delivered concurrently with wins, and scaled in salience with reward size, significantly more rats preferred the risky options as compared to the uncued rGT. Similar results were observed when the relationship between reward size and cue complexity was inverted, and when cues were delivered concurrently with all outcomes. Conversely, risky choice did not increase when cues occurred randomly on 50% of trials, and decision making actually improved when cues were coincident with losses alone. As such, cues do not increase risky choice by simply elevating arousal, or amplifying the difference between wins and losses. It is instead important that the cues are reliably associated with wins; presenting the cues on losing outcomes as well as wins does not diminish their ability to drive risky choice. Computational analyses indicate that win-paired cues reduced the impact of losses on decision making. These results may help us understand how sensory stimulation can increase the addictive nature of gambling and gaming products.

Sex differences in motivation for food rewards, gambling, and drugs of abuse are modulated by multiple factors, including sensory stimuli, gonadal hormones, and cognitive bias. Cues, drugs of abuse, and a high-fat diet can significantly impact neural signaling in the reward system and functioning of neural systems that regulate executive functions differentially in males and females. Additionally, sex differences in risky decision-making, cognitive bias, and motivation for food and drugs of abuse are mediated by gonadal hormones in both sexes. As neuroscientists analyze data from both sexes, it is becoming apparent that these differences are not simply mediated by hormones in females, but involve sex differences in the specific neural responses to stimuli, including both external stimuli and internal hormonal signals. Understanding sex differences in the mechanisms underlying reward-seeking behaviors and the development of substance use disorders will help uncover potential therapies and treatments that will benefit both men and women. Based on these observations, it is essential that females are included in neuroscience research.

Dopamine D2/3 receptor agonists are less likely to trigger dyskinesias than L-dopa while still offering relief from the motor symptoms of Parkinson's disease (PD). However, these drugs can cause serious impulse control problems and gambling disorders. Adjunctive therapies capable of blocking these side effects without impacting the antiparkinsonian effect would be clinically useful. G-protein-coupled receptor 52 (GPR52) is an orphan Gs-protein-coupled receptor that is coexpressed with striatal D₂ receptors. Activating GPR52 attenuates behaviors associated with increased striatal dopamine release without altering basal function. Iatrogenic gambling disorder may be mediated, at least partly, by striatal dopamine signaling. We therefore investigated whether 2 potent small-molecule GPR52 agonists (BD442618, BD502657) could block the increase in preference for uncertain outcomes caused by acute d-amphetamine and chronic ropinirole, without altering baseline choice patterns. In the rat betting task (rBT), subjects choose between a guaranteed reward (the "wager") versus the 50:50 chance of double the wager or nothing. Although wager size varies across trial blocks, both options are constantly matched for expected value. The effects of BD442618 on the rBT were acutely assessed alone or in combination with d-amphetamine and subsequently in combination with chronic ropinirole. The latter experiment was then repeated with BD502657. BD442618 did not alter baseline decision making but attenuated the increase in preference for uncertainty caused by both acute amphetamine and chronic ropinirole administration. Similarly, BD502657 abrogated chronic ropinirole's effects. These data provide the first evidence that GPR52 agonists may be useful in treating iatrogenic gambling disorder or other conditions hallmarked by hyperdopaminergic states. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

International audience; The subthalamic nucleus (STN) is known to play a role in the control of impulsivity of action and in impulsivity of choice under certain conditions. In order to assess its influence on decision-making under uncertainty, we have tested here the effects of bilateral STN lesions in rats performing a probability discounting task (PDT) and a "loss-chasing" task, both tasks assessing risky decision under uncertainty, but one in a positive context (probability to obtain a larger reward) and the other in a negative context (risk for a larger loss). The PDT measures the choice between a small certain and a large uncertain reward. Conversely, in the "loss-chasing" task, animals choose between accepting a small certain loss versus risking a larger but uncertain penalty. The results show that STN lesions reduce risk-taking in both the PDT and the loss-chasing task, suggesting that STN inactivation could decrease risky decision-making whatever the nature of the outcome in an ambiguous context. Interestingly, opposite results were found in a small number of animals for which the lesions extended to the area dorsal to the STN (in the zona incerta), such that these animals increased choice of the uncertain option in the PDT. These results confirm the specificity of STN involvement in these processes and may provide explanations for some side-effects reported in patients when STN manipulations extend to the Zona Incerta. They also support the choice of the STN as a target for the treatment of impulse control disorders in Parkinson's disease and in obsessive compulsive disorders.

Rationale Problematic patterns of gambling are characterised by loss of control and persistent gambling often to recover losses. However, little is known about the mechanisms that mediate initial choices to begin gambling and then continue to gamble in the face of losing outcomes. Objectives These experiments first assessed gambling and loss-chasing performance under different win/lose probabilities in C57Bl/6 mice, and then investigated the effects of antagonism of 5-HT2CR with SB242084, 5-HT1AR agonism with 8-OH-DPAT and modafinil, a putative cognitive enhancer. Results As seen in humans and other species, mice demonstrated the expected patterns of behaviour as the odds for winning were altered increasing gambling and loss-chasing when winning was more likely. SB242084 decreased the likelihood to initially gamble, but had no effects on subsequent gambling choices in the face of repeated losses. In contrast, 8-OH-DPAT had no effects on choosing to gamble in the first place, but once started 8-OH-DPAT increased gambling choices in a dose-sensitive manner. Modafinil effects were different to the serotonergic drugs in both decreasing the propensity to initiate gambling and chase losses. Conclusions We present evidence for dissociable effects of systemic drug administration on different aspects of gambling behaviour. These data extend and reinforce the importance of serotonergic mechanisms in mediating discrete components of gambling behaviour. They further demonstrate the ability of modafinil to reduce gambling behaviour. Our work using a novel mouse paradigm may be of utility in modelling the complex psychological and neurobiological underpinnings of gambling problems, including the analysis of genetic and environmental factors.

Background: Individuals must frequently evaluate whether it is worth allocating cognitive effort for desired outcomes. Motivational deficits are a common feature of psychiatric illness such as major depression. Selective serotonin reuptake inhibitors are commonly used to treat this disorder, yet some data suggest these compounds are ineffective at treating amotivation, and may even exacerbate it. Aims: Here we used the rodent Cognitive Effort Task (rCET) to assess serotonergic (5-hydroxytryptamine, 5-HT) contributions to decision-making with cognitive effort costs. Methods: The rCET is a modified version of the 5-choice serial reaction time task, a well-validated test of visuospatial attention and impulse control. At the start of each rCET trial, rats chose one of two levers, which set the difficulty of an attentional challenge, namely the localization of a visual stimulus illuminated for 0.2 or 1 s on hard versus easy trials. Successful completion of hard trials was rewarded with double the sugar pellets. Twenty-four female Long–Evans rats were trained on the rCET and systemically administered the 5-HT1A agonist 8-OH-DPAT, the 5-HT2A antagonist M100907, the 5-HT2C agonist Ro-60-0175, as well as the 5-HT2C antagonist SB 242, 084. Results: 5-HT2A antagonism dose-dependently reduced premature responding, while 5-HT2C antagonism had the opposite effect. 8-OH-DPAT impaired accuracy of target detection at higher doses, while Ro-60-0175 dose-dependently improved accuracy on difficult trials. However, none of the drugs affected the rats’ choice of the harder option. Conclusion: When considered with existing work evaluating decision-making with physical effort costs, it appears that serotonergic signalling plays a minor role in guiding effort allocation.

Social isolation is an established risk factor for mental illness and impaired immune function. Evidence suggests that neuroinflammatory processes contribute to mental illness, possibly via cytokine-induced modulation of neural activity. We examined the effects of lipopolysaccharide (LPS) administration and social home cage environment on cognitive performance in the 5-Choice Serial Reaction Time Task (5CSRTT), and their effects on corticosterone and cytokines in serum and brain tissue. Male Long-Evans rats were reared in pairs or in isolation before training on the 5CSRTT. The effects of saline and LPS (150 µg/kg i.p.) administration on sickness behaviour and task performance were then assessed. LPS-induced sickness behaviour was augmented in socially-isolated rats, translating to increased omissions and slower response times in the 5CSRTT. Both social isolation and LPS administration reduced impulsive responding, while discriminative accuracy remained unaffected. With the exception of reduced impulsivity in isolated rats, these effects were not observed following a second administration of LPS, revealing behavioural tolerance to repeated LPS injections. In a separate cohort of animals, social isolation potentiated the ability of LPS to increase serum corticosterone and IL-6, which corresponded to increased IL-6 in the orbitofrontal and medial prefrontal cortices and the nucleus accumbens. Basal IL-4 levels in the nucleus accumbens were reduced in socially-isolated rats. These findings are consistent with the adaptive response of reduced motivational drive following immune challenge, and identify social isolation as an exacerbating factor. Enhanced IL-6 signalling may play a role in mediating the potentiated behavioural response to LPS administration in isolated animals.

Previous research has indicated that reward-paired cues can enhance disadvantageous risky choice in both humans and rodents. Systemic administration of a serotonin 2C receptor antagonist can attenuate this cue-induced risk preference in rats. However, the neurocognitive mechanisms mediating this effect are currently unknown. We therefore assessed whether the serotonin 2C receptor antagonist RS 102221 is able to attenuate cue-enhanced risk preference via its actions in the lateral orbitofrontal cortex (lOFC) or prelimbic (PrL) area of the medial prefrontal cortex (mPFC). A total of 32 male Long–Evans rats were trained on the cued version of the rat gambling task (rGT), a rodent analog of the human Iowa gambling task, and bilateral guide cannulae were implanted into the lOFC or PrL. Intra-lOFC infusions of the 5-HT2C antagonist RS 102221 reduced risky choice in animals that showed a preference for the risky options of the rGT at baseline. This effect was not observed in optimal decision-makers, nor those that received infusions targeting the PrL. Given prior data showing that 5-HT2C antagonists also improve reversal learning through the same neural locus, we hypothesized that reward-concurrent cues may amplify risky decision-making through cognitive inflexibility. We therefore devalued the sugar pellet rewards used in the cued rGT (crGT) through satiation and observed that decision-making patterns did not shift unless animals also received intra-lOFC RS 102221. Collectively, these data suggest that the lOFC is one critical site through which reward-concurrent cues promote risky choice patterns that are insensitive to reinforcer devaluation, and that 5-HT2C antagonism may optimize choice by facilitating exploration. Significance Statement Lights and sounds signaling reward are used extensively in electronic gaming machines. Recent data indicate that these win-associated cues can increase disadvantageous risky choice. Administering a serotonin 2C receptor antagonist can ameliorate this effect in rats, potentially by increasing flexibility in decision-making. The orbitofrontal cortex (OFC) is critically involved in mediating flexible behavior. Thus, the present study evaluated whether serotonin 2C antagonism in the OFC can reduce disadvantageous risky choice via alterations to behavioral flexibility. Results implicate the OFC as one critical locus, and an increase in flexibility as a potential cognitive mechanism, through which cue-enhanced risky decision-making may improve. This could point to potential therapeutic interventions for problematic gambling that target the control of cues over behavior.

Traumatic brain injury (TBI) affects at least 3 M people annually. In humans, repetitive mild TBI (rmTBI) can lead to increased impulsivity and may be associated with chronic traumatic encephalopathy. To better understand the relationship between repetitive TBI (rTBI), impulsivity and neuropathology, we used CHIMERA (Closed-Head Injury Model of Engineered Rotational Acceleration) to deliver five TBIs to rats, which were continuously assessed for trait impulsivity using the delay discounting task and for neuropathology at endpoint. Compared to sham controls, rats with rTBI displayed progressive impairment in impulsive choice. Histological analyses revealed reduced dopaminergic innervation from the ventral tegmental area to the olfactory tubercle, consistent with altered impulsivity neurocircuitry. Consistent with diffuse axonal injury generated by CHIMERA, white matter inflammation, tau immunoreactivity and degeneration were observed in the optic tract and corpus callosum. Finally, pronounced grey matter microgliosis was observed in the olfactory tubercle. Our results provide insight into the mechanisms by which rTBI leads to post-traumatic psychiatric-like symptoms in a novel rat TBI platform.

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 STATEMENTImpaired 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.

Multiline slot machines encourage continued play through 'losses disguised as wins' (LDWs), outcomes in which the money returned is less than that wagered. Individuals with gambling problems may be susceptible to this game feature. The cognitive and neurobiological mechanisms through which LDWs act are unknown. In a novel rat operant task, animals chose between a 'certain' lever, which always delivered two sugar pellets, or an 'uncertain' lever, resulting in four sugar pellets on 50% of trials. LDWs were then introduced as a return of three sugar pellets on 30-40% of uncertain rewarded trials. For half the rats, winning outcomes were paired with audiovisual feedback (cues). In a second study, the basolateral amygdala (BLA) was inactivated during initial presentation of LDWs. While LDWs shifted most rats' choice toward the certain lever, a subgroup of LDW vulnerable rats continued to choose the uncertain option, when the reward rate diminished. This profile of LDW vulnerability was reproduced after inactivating the BLA. Persistent choice of uncertain outcomes despite lower reward rates may reflect impaired functioning within the BLA. Future work using this model may provide insight into the neurobiological mechanisms contributing to the motivational properties of LDWs and their contribution to problematic gambling.

Background: Pairing rewards with sensory stimulation, in the form of auditory and visual cues, increases risky decision-making in both rats and humans. Understanding the neurobiological basis of this effect could help explain why electronic gambling machines are so addictive, and inform treatment development for compulsive gambling and gaming. Numerous studies implicate the dopamine system in mediating the motivational influence of reward-paired cues; recent data suggest the cholinergic system also plays a critical role. Previous work also indicates that cholinergic drugs alter decision-making under uncertainty. Aims: We investigated whether the addition of reward-concurrent cues to the rat gambling task (crGT) altered the effects of peripherally administered cholinergic compounds. Methods: Muscarinic and nicotinic agonists and antagonists were administered to 16 male, Long–Evans rats trained on the crGT. Measures of optimal/risky decision-making and motor impulsivity were the main dependent variables of interest. Results: The muscarinic receptor antagonist scopolamine improved decision-making overall, decreasing selection of one of the risky options while increasing choice of the more advantageous options. The muscarinic agonist oxotremorine increased choice latency but did not significantly affect option preference. Neither the nicotinic antagonist mecamylamine nor the agonist nicotine affected choice patterns, but mecamylamine decreased premature responding, an index of motor impulsivity. Conclusions: These results contrast sharply from those obtained previously using the uncued rGT, and suggest that the deleterious effects of win-paired cues on decision-making and impulse control may result from elevated cholinergic tone.

Gambling and substance use disorders are highly comorbid. Both clinical populations are impulsive and exhibit risky decision-making. Drug-associated cues have long been known to facilitate habitual drug-seeking, and the salient audiovisual cues embedded within modern gambling products may like-wise encourage problem gambling. The dopamine neurons of the ventral tegmental area (VTA) are exquisitely sensitive to drugs of abuse, uncertain rewards, and reward-paired cues, and may therefore be the common neural substrate mediating synergistic features of both disorders. To test this hypothesis, we first gained specific inhibitory control over VTA dopamine neurons by transducing a floxed inhibitory DREADD (AAV5-hSyn-DIO-hM4D(Gi)-mCherry) in rats expressing Cre recombinase in tyrosine hydroxylase neurons. We then trained rats in our cued rat gambling task (crGT), inhibiting dopamine neurons throughout task acquisition and performance, before allowing them to self-administer cocaine in the same diurnal period as crGT sessions. The trajectories of addiction differ in women and men, and the dopamine system may differ functionally across the sexes, therefore we used male and female rats here. We found that inhibition of VTA dopamine neurons decreased cue-induced risky choice and reduced motor impulsivity in males, but surprisingly, enhanced risky decision making in females. Inhibiting VTA dopamine neurons also prevented cocaine-induced deficits in decision making in both sexes, but nevertheless drove all animals to consume more cocaine. These findings show that chronic dampening of dopamine signalling can have both protective and deleterious effects on addiction-relevant behaviours, depending on biological sex and dependent variable of interest.

The flashing lights and sounds of modern casinos are alluring and may contribute to the addictive nature of gambling. Such cues can have a profound impact on the noradrenaline (NA) system, which could therefore be a viable therapeutic target for gambling disorder (GD). While there is substantial evidence to support the involvement of NA in the impulsive symptoms of GD, its function in mediating the “pro-addictive” impact of cues is less understood. We wished to investigate the role of NA in our rodent assay of decision making and impulsivity, the cued rat gambling task (crGT). Given that sex differences are prominent in addiction disorders, and increasingly reported in the monoaminergic regulation of behaviour, we also prioritised evaluating noradrenergic drugs in both sexes. Female and male rats were trained to stability on the crGT and then given intraperitoneal injections of the noradrenaline reuptake inhibitor atomoxetine, the α2A receptor agonist guanfacine, the beta receptor antagonist propranolol, and the α2 receptor antagonist yohimbine. Atomoxetine dose-dependently improved decision-making score. Guanfacine selectively enhanced decision making in risk-preferring males and optimal performing females. Propranolol and yohimbine did not influence decision making. Atomoxetine and guanfacine reduced premature responses, while yohimbine bi-phasically affected this index of motor impulsivity. These results support the hypothesis that NA is an important neuromodulator of the cue-induced deficits in decision making observed in laboratory-based gambling paradigms, and suggest that NAergic drugs like atomoxetine and guanfacine may be useful in treating GD.

Women and men can differ in their propensity to take risks and develop impulse control and addiction disorders. Sexual dimorphisms in behavioral control by the mesolimbic dopaminergic reward system may underlie these phenomena, given its sensitivity to gonadal hormones. However, this is hard to test experimentally using humans. Using the rat gambling task (rGT), we investigated what impact acute inhibition of accumbal dopamine had on decision-making and impulsivity in animals of both sexes. We expressed an inhibitory designer receptor exclusively activated by designer drugs (hM4D[Gi]) in the accumbal dopaminergic efferents of female and male transgenic (Tg) rats, engineered to selectively express cre recombinase in neurons synthesizing tyrosine hydroxylase. We then trained the rats to perform the rGT and assessed the effect of an acute clozapine-n-oxide (0-3 mg/kg) challenge. Chemogenetic inhibition of dopaminergic projections to the accumbens did not affect choice in females, perhaps due to low levels of risky choice in Tg+ animals at baseline, but induced a switch from risky to optimal decision-making in males performing the cued rGT. This manipulation also decreased motor impulsivity but only in females. These data support the hypothesis that cue-driven risky choice is mediated, at least in males, by activity of accumbal dopaminergic neurons. However, motor impulsivity is more sensitive to inhibition of accumbal dopamine neurons in female rats. These data may help explain differences in the manifestation of addictions across gender and reinforce the importance of examining both sexes when seeking to attribute control of behavior to specific monoaminergic pathways. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Organisms must frequently evaluate the amount of effort to invest in pursuing future rewards. Despite explicit awareness of the potential benefits of cognitive work, individuals vary in their willingness to attempt cognitively demanding tasks, regardless of intellectual ability. Such differences may suggest that the degree to which cognitive effort degrades perceived outcome value is a subjective, rather than objective, process, similar to risk and delay discounting. Although numerous studies suggest the orbitofrontal cortex (OFC) is important for allowing subjective value estimates to be updated and/or used in cost/benefit decision-making, the causal role of the OFC in valuations of mental effort has received scant investigation. We therefore trained 24 female Long-Evans rats on the rodent cognitive effort task (rCET) and assessed performance following temporary bilateral inactivation of the ventrolateral OFC (vlOFC). In the rCET, rats decide at trial outset whether to perform an easy or hard attentional challenge, namely to localize a brief visual stimulus to one of five possible locations. The difficulty of the challenge is determined by the stimulus duration (1.0 vs. 0.2s for easy vs. hard trials respectively), and success on hard trials results in double the sugar pellet rewards. Somewhat surprisingly, inactivations of the vlOFC did not affect rats' willingness or ability to exert cognitive effort for larger rewards, despite increasing omissions and motor impulsivity on-task. When considered with previous work, it appears the vlOFC plays a minimal role in cognitive effort allocation specifically, and in valuations of effort more generally.

Impairments in decision making under uncertainty, as measured by the Iowa Gambling Task (IGT), are observed in persons suffering from temporal lobe epilepsy (TLE), in which seizures originate in the amygdala and hippocampal formations. Gambling disorder is also more prevalent in this population. Individuals with amygdala damage show similar deficits in decision-making, as do rats with lesions restricted to the basolateral amygdala (BLA) performing an analogous rat gambling task (rGT), yet whether hyperstimulation of the BLA impacts risky decision-making has yet to be demonstrated. We therefore investigated whether kindling of the BLA affected rGT performance. In this task, sugar pellet profits are maximised through consistent selection of options associated with smaller per-trial gains but shorter punishing time-outs. Just as in the IGT, subjects must avoid the risky options, as penalties are disproportionately high despite the higher reward available. Most rats adopt the optimal strategy, but some instead make high numbers of risky, disadvantageous choices. Once stable choice preferences had been established on-task, sixteen male Long Evans rats were implanted unilaterally with a bipolar electrode targeting the BLA and stimulated twice daily until three stage five seizures had been elicited. The electrodes revealed to be nearly evenly places in the BLA and the Central Nucleus of the Amygdala (CeA). Kindling transiently increased choice of the option paired with the smallest reward but also the lowest level of punishment- a risk-averse, but suboptimal, choice. Risk-preferring rats also made more premature responses, a marker of motor impulsivity, and were faster to make a choice, whereas these variables were unaffected in optimal decision-makers. These data suggest epileptiform activity originating within the amygdala can impair choice and promote impulsivity, at least in some individuals.

Lithium’s efficacy in reducing both symptom severity in bipolar disorder (BD) and suicide risk across clinical populations may reflect its ability to reduce impulsivity. Changes in immune markers are associated with BD and suicidality yet their exact role in symptom expression remains unknown. Evidence also suggests that lithium may decrease levels of pro-inflammatory cytokines in the periphery and central nervous system, and that such changes are related to its therapeutic efficacy. However, issues of cause and effect are hard to infer from clinical data alone. Here, we investigated the effects of chronic dietary lithium treatment on rats’ performance of the 5-Choice Serial Reaction Time Task (5CSRTT), a well-validated operant behavioural task measuring aspects of impulsivity, attention and motivation. Male Long-Evans rats received a diet supplemented with 0.3% LiCl (n = 13), or the equivalent control diet (n = 16), during behavioural testing. Blood and brain tissue samples were assayed for a wide range of cytokines once any changes in impulsivity became significant. After 12 weeks, chronic lithium treatment reduced levels of motor impulsivity, as indexed by premature responses in the 5CSRTT; measures of sustained attention and motivation were unaffected. Plasma levels of IL-1β, IL-10 and RANTES (CCL-5) were reduced in lithium-treated rats at this time point. IL-1β, IL-6 and RANTES were also reduced selectively within the orbitofrontal cortex of lithium-treated rats, whereas cytokine levels in the medial prefrontal cortex and nucleus accumbens were comparable with control subjects. These results are consistent with the hypothesis that lithium may improve impulse control deficits in clinical populations by minimising the effects of pro-inflammatory signalling on neuronal activity, particularly within the orbitofrontal cortex.

Current methods using a single PET scan to detect voxel-level transient dopamine release—using F-test (significance) and cluster size thresholding—have limited detection sensitivity for clusters of release small in size and/or having low release levels. Specifically, simulations show that voxels with release near the peripheries of such clusters are often rejected—becoming false negatives and ultimately distorting the F-distribution of rejected voxels. We suggest a Monte Carlo method that incorporates these two observations into a cost function, allowing erroneously rejected voxels to be accepted under specified criteria. In simulations, the proposed method improves detection sensitivity by up to 50% while preserving the cluster size threshold, or up to 180% when optimizing for sensitivity. A further parametric-based voxelwise thresholding is then suggested to better estimate the release dynamics in detected clusters. We apply the Monte Carlo method to a pilot scan from a human gambling study, where additional parametrically unique clusters are detected as compared to the current best methods—results consistent with our simulations.

Reward-related stimuli can potently influence behavior; for example, exposure to drug-paired cues can trigger drug use and relapse in people with addictions. Psychological mechanisms that generate such outcomes likely include cue-induced cravings and attentional biases. Recent animal data suggest another candidate mechanism: reward-paired cues can enhance risky decision making, yet whether this translates to humans is unknown. Here, we examined whether sensory reward-paired cues alter decision making under uncertainty and risk, as measured respectively by the Iowa Gambling Task and a two-choice lottery task. In the cued versions of both tasks, gain feedback was augmented with reward-concurrent audiovisual stimuli. Healthy human volunteers (53 males, 78 females) performed each task once, one with and the other without cues (cued Iowa Gambling Task/uncued Vancouver Gambling Task:n= 63; uncued Iowa Gambling Task/cued Vancouver Gambling Task:n= 68), with concurrent eye-tracking. Reward-paired cues did not affect choice on the Iowa Gambling Task. On the two-choice lottery task, the cued group displayed riskier choice and reduced sensitivity to probability information. The cued condition was associated with reduced eye fixations on probability information shown on the screen and greater pupil dilation related to decision and reward anticipation. This pupil effect was unrelated to the risk-promoting effects of cues: the degree of pupil dilation for risky versus risk-averse choices did not differ as a function of cues. Together, our data show that sensory reward cues can promote riskier decisions and have additional and distinct effects on arousal.SIGNIFICANCE STATEMENTAnimal data suggest that reward-paired cues can promote maladaptive reward-seeking by biasing cost-benefit decision making. Whether this finding translates to humans is unknown. We examined the effects of salient reward-paired audiovisual cues on decision making under risk and uncertainty in human volunteers. Cues had risk-promoting effects on a risky choice task and independently increased task-related arousal as measured by pupil dilation. By demonstrating risk-promoting effects of cues in human participants, our data identify a mechanism whereby cue reactivity could translate into maladaptive behavioral outcomes in people with addictions.

Traumatic brain injury (TBI) has been linked to the development of numerous psychiatric diseases, including substance use disorder. However, it can be difficult to ascertain from clinical data whether the TBI is cause or consequence of increased addiction vulnerability. Surprisingly few studies have taken advantage of animal models to investigate the causal nature of this relationship. In terms of a plausible neurobiological mechanism through which TBI could magnify the risk of substance dependence, numerous studies indicate that TBI can cause widespread disruption to monoaminergic signaling in striatal regions, and also increases neuroinflammation. In the current study, male Long-Evans rats received either a mild or severe TBI centered over the frontal cortex via controlled cortical impact, and were subsequently trained to self-administer cocaine over ten six-hour sessions. At the end of the study, markers of striatal dopaminergic function, and levels of inflammatory cytokine levels in the frontal lobes, were assessed via western blot and multiplex ELISA, respectively. There was significantly higher cocaine intake in a subset of animals with either mild or severe TBI. However, many animals within both TBI groups failed to acquire self-administration. Principal components analysis suggested that both dopaminergic and neuroinflammatory proteins were associated with overall cocaine intake, yet only an inflammatory component was associated with acquisition of self-administration, suggesting neuroinflammation may make a more substantial contribution to the likelihood of drug-taking. Should neuroinflammation play a causal role in mediating TBI-induced addiction risk, anti-inflammatory therapy may reduce the likelihood of substance abuse in TBI populations.

Evidence suggests that impulse control deficits contribute to excessive food intake in some individuals with obesity. In addition to its known role in regulating appetite and glucose metabolism, the hormone leptin also directly modulates the activity of central dopamine systems. Although dopamine is involved in regulating impulsivity, the influence of leptin per se on this cognitive domain remains unclear. This study explored the performance of male leptin knockout (KO) and wild type (WT) rats in the 5-Choice Serial Reaction Time task (5CSRTT) of motor impulsivity and visuospatial attention. Behavioural performance was assessed under baseline conditions, following 4 weeks high-fat diet (HFD; 60 kcal%) consumption, and after acute pharmacological challenge with the indirect dopamine agonist, amphetamine. Subjects were also tested for glucose tolerance and insulin sensitivity, and dorsal and ventral striatal tissue was assayed ex vivo for markers of dopaminergic transmission. Obese KO rats learned the 5CSRTT at a slower rate compared to WT rats, in a manner suggestive of mild attentional impairment. However, task performance at baseline and after HFD intake was similar to that of WT controls. HFD intake reduced omissions across all subjects, whereas amphetamine challenge revealed a prominent genotype effect on 5CSRTT performance, with potentiated levels of impulsive responding and faster response times in KO rats compared to WT animals. Effects of amphetamine on other variables were similar between genotypes. Notably, the expression of striatal dopaminergic markers was unchanged in KO rats, and neither chronic food restriction nor HFD intake altered the impairments in glucose or insulin metabolism previously reported in these animals. These data suggest that leptin deficiency enhances impulsive action under conditions of dopaminergic challenge, yet this seems independent of overt changes in the expression of post-synaptic markers of dopamine signalling in striatal regions.

Obesity is a world-wide crisis with profound healthcare and socio-economic implications and it is now clear that the central nervous system (CNS) is a target for the complications of metabolic disorders like obesity. In addition to decreases in physical activity and sedentary lifestyles, diet is proposed to be an important contributor to the etiology and progression of obesity. Unfortunately, there are gaps in our knowledge base related to how dietary choices impact the structural and functional integrity of the CNS. For example, while chronic consumption of hypercaloric diets (increased sugars and fat) contribute to increases in body weight and adiposity characteristic of metabolic disorders, the mechanistic basis for neurocognitive deficits in obesity remains to be determined. In addition, studies indicate that acute consumption of hypercaloric diets impairs performance in a wide variety of cognitive domains, even in normal non-obese control subjects. These results from the clinical and basic science literature indicate that diet can have rapid, as well as long lasting effects on cognitive function. This review summarizes our symposium at the 2017 Society for the Study of Ingestive Behavior (SSIB) meeting that discussed these effects of diet on cognition. Collectively, this review highlights the need for integrated and comprehensive approaches to more fully determine how diet impacts behavior and cognition under physiological conditions and in metabolic disorders like type 2 diabetes mellitus (T2DM) and obesity.

Rationale Problematic patterns of gambling are characterised by loss of control and persistent gambling often to recover losses. However, little is known about the mechanisms that mediate initial choices to begin gambling and then continue to gamble in the face of losing outcomes. Objectives These experiments first assessed gambling and loss-chasing performance under different win/lose probabilities in C57Bl/6 mice, and then investigated the effects of antagonism of 5-HT2CR with SB242084, 5-HT1AR agonism with 8-OH-DPAT and modafinil, a putative cognitive enhancer. Results As seen in humans and other species, mice demonstrated the expected patterns of behaviour as the odds for winning were altered increasing gambling and loss-chasing when winning was more likely. SB242084 decreased the likelihood to initially gamble, but had no effects on subsequent gambling choices in the face of repeated losses. In contrast, 8-OH-DPAT had no effects on choosing to gamble in the first place, but once started 8-OH-DPAT increased gambling choices in a dose-sensitive manner. Modafinil effects were different to the serotonergic drugs in both decreasing the propensity to initiate gambling and chase losses. Conclusions We present evidence for dissociable effects of systemic drug administration on different aspects of gambling behaviour. These data extend and reinforce the importance of serotonergic mechanisms in mediating discrete components of gambling behaviour. They further demonstrate the ability of modafinil to reduce gambling behaviour. Our work using a novel mouse paradigm may be of utility in modelling the complex psychological and neurobiological underpinnings of gambling problems, including the analysis of genetic and environmental factors. Electronic supplementary material The online version of this article (10.1007/s00213-020-05496-x) contains supplementary material, which is available to authorized users.

Background: Deficits in impulse control feature in many psychiatric conditions including bipolar disorder, suicidality and addictions. Lithium lowers impulsivity in clinical populations and decreases pathological gambling in experimental medicine studies, but suffers from adverse effects, poor compliance and a low therapeutic index. Aims: Recently we identified that the neuroprotective agent ebselen, which is reportedly safe in humans, inhibited inositol monophosphatase (IMPase), a candidate lithium mechanism. Ebselen also reduced 5-HT receptor (5-HT2A) function which predicts impulsivity lowering properties. Here we investigated the effect of ebselen in rat models of impulsive behaviour. Methods: Ebselen was tested in two models of impulsivity with human analogues: the five-choice serial reaction time task (5-CSRTT) and rodent gambling task (rGT). The main outcome measures were premature responses (5-CSRTT and rGT) and choice behaviour (rGT), which model motor impulsivity and choice impulsivity, respectively. Results: At doses that decreased 5-HT2A receptor function (DOI-induced wet dog shakes), ebselen decreased premature responding in the 5-CSRTT both in the absence and presence of cocaine. The 5-HT2A receptor antagonist MDL 100,907 also reduced premature responding in the 5-CSRTT although not in the presence of cocaine. In the rGT ebselen showed a tendency to reduce premature responding but had no effect on choice behaviour. Conclusions: These findings suggest that ebselen preferentially reduces motor impulsivity over choice impulsivity, and that inhibition of 5-HT2A receptor function is a contributing mechanism. Collectively, these data support the repurposing of ebselen as an anti-impulsive treatment and fast-tracking to clinical trials in patient groups characterised by poor impulse control.

Rationale Adding reward-concurrent cues to a rat gambling task (rGT) increases risky choice. This cued version of the task may reflect an “addiction-like” cognitive process, more similar to human gambling than the uncued task. Serotonergic drugs that target 5-HT2 receptors alter mechanisms linked to impulse control. However, relatively little is known regarding the impact of such agents on either risky decision making, or the ability of conditioned stimuli to bias the choice process, despite potential relevance to addiction development and treatment. Objectives The aim of this study was to determine the effects of SB 242,084 and M100907, selective antagonists at the 5-HT2C and 5-HT2A receptors respectively, as well as the selective 5-HT2C receptor agonist Ro-60-0175, on performance of both cued and uncued versions of the rGT. Results SB 242,084 significantly and dose-dependently increased choice of the most optimal option in the cued rGT only, despite concurrently increasing impulsive responses made prematurely on both the cued and uncued rGT. M100907 and Ro-60-0175 did not alter risky decision making, but nevertheless produced the expected decrease in premature responses on both task variants. Conclusions These findings demonstrate that the 5-HT2 receptor-mediated regulation of risky decision making and motor impulsivity can be pharmacologically dissociated and further show that the presence of highly salient reward-paired cues critically alters the neurochemical regulation of the choice process. Importantly, these results suggest that 5-HT2C receptor antagonists may be of use in disrupting maladaptive patterns of decision making.

The α2-adrenoceptor antagonist, yohimbine, is commonly used as a pharmacological stressor. Its behavioural effects are typically attributed to elevated noradrenaline release via blockade of central, inhibitory autoreceptors. We have previously reported that yohimbine increases motor impulsivity in rats on the five-choice serial reaction time task (5CSRTT), a cognitive behavioural assessment which measures motor impulsivity and visuospatial attention. Furthermore, this effect depended on cyclic adenomonophosphate (cAMP) signalling via cAMP response element binding (CREB) protein in the orbitofrontal cortex (OFC). However, the role of specific adrenoceptors in this effect is not well-characterised. We therefore investigated whether the pro-impulsive effects of systemic yohimbine could be reproduced by direct administration into the OFC, or attenuated by intra-OFC or systemic administration of prazosin and propranolol-antagonists at the α1- and β-adrenoceptor, respectively. Male Long-Evans rats were trained on the 5CSRTT and implanted with guide cannulae aimed at the OFC. Systemically administered α1- or β-adrenoceptor antagonists attenuated yohimbine-induced increases in premature responding. In contrast, local infusion of yohimbine into the OFC reduced such impulsive responding, while blockade of α1- or β-adrenoceptors within the OFC had no effect on either basal or yohimbine-stimulated motor impulsivity. Direct administration of selective antagonists at the α1-, α2- or β-adrenoceptor into the OFC therefore produce clearly dissociable effects from systemic administration. Collectively, these data suggest that the pro-impulsivity effect of yohimbine can be modulated by adrenergic signalling in brain areas outside of the OFC, in addition to non-adrenergic signalling pathways within the OFC.

Impulsivity is thought to contribute to the development and maintenance of gambling disorder, but the mechanistic relationship between these complex and multifaceted behaviors is unclear. Animal models have been developed to examine various aspects of each, and have provided insight into the specific contributions of individual brain regions. Silencing distinct cortical and striatal regions within the affective corticostriatal loop can increase impulsivity and risky decision making, but the correspondence between various forms of both impulsivity and choice is imperfect. Instead, it appears that different facets of impulsivity and gambling-like behavior result from constellations of component processes. Such information may prove useful in understanding how risky decision making and impulsive behaviors interact in clinical conditions such as gambling disorder.

Primary Objective: Traumatic brain injury (TBI) is associated with numerous psychiatric comorbidities, and subclinical psychiatric symptoms. While many symptoms have been replicated in animal models of brain injury, a vast majority of studies utilize naive rats as subjects, which fail to mimic the complex learning history of human patients.Methods and Procedures: In the current study, we evaluated the effects of a brain injury in animals with early exposure to uncertainty on post-injury decision-making in a probabilistic task, the rodent gambling task (RGT).Main Outcomes and Results: Exposure to uncertainty resulted in a heterogeneous sample relative to prior publications, and brain-injured rats showed no deficits in choice behavior compared to shams which contrasts with large, pervasive deficits in previously published work. However, TBI increased impulsivity and caused transient changes in behavioral variables indicative of initial motivational deficits (pellets earned, omitted responses). Notably, effects of amphetamine were similar on this heterogeneous sample of rats relative to a number of other published reports, suggesting consistent effects of gross monoaminergic manipulations on choice behavior, independent of experience.Conclusions: Going forward, translational studies need to consider the heterogeneity that exists at the clinical level and account for these problems when modeling diseases in animals.

International audience; Rationale Chronic administration of D 2/3 receptor agonists ropinirole or pramipexole can increase the choice of uncertain rewards in rats, theoretically approximating iatrogenic gambling disorder (iGD). Objectives We aimed to assess the effect of chronic ropinirole in animal models that attempt to capture critical aspects of commercial gambling, including the risk of losing rather than failing to gain, and the use of win-paired sensory stimuli heavily featured in electronic gambling machines (EGMs). Methods Male Long-Evans rats learned the rat gambling task (rGT; n = 24), in which animals sample between four options that differ in the magnitude and probability of rewards and time-out punishments. In the cued rGT (n = 40), reward-concurrent audiovisual cues were added that scaled in complexity with win size. Rats were then implanted with an osmotic pump delivering ropinirole (5 mg/kg/day) or saline for 28 days. Results Chronic ropinirole did not unequivocally increase preference for more uncertain outcomes in either the cued or uncued rGT. Ropinirole transiently increased premature responses, a measure of motor impulsivity, and this change was larger and more long-lasting in the cued task. Conclusions These data suggest that explicitly signaling loss prevents the increase in preference for uncertain rewards caused by D 2/3 receptor agonists observed previously. The ability of win-paired cues to amplify ropinirole-induced increases in motor impulsivity may explain why compulsive use of EGMs is particularly common in iGD. These data offer valuable insight into the cognitive-behavioral mechanisms through which chronic dopamine agonist treatments may induce iGD and related impulse control disorders.

Foraging and operant models suggest that animals will tolerate uncertainty or risk to obtain food quickly. In modern food environments, sustained access to quick energy-dense foods can promote weight gain. Here, we used a discrete-choice procedure to examine peoples' decisions about when next to eat high-value, palatable food rewards, probabilistically delivered immediately or following longer delays. In Experiment 1, moderately hungry young females showed consistent preferences for a variable delay option that delivered food rewards immediately or following long delays over a fixed delay option that delivered the same rewards following intermediate delays. These preferences were stronger in females with higher BMIs compared with lower BMIs, suggesting that quick food can enhance the value of uncertain or ‘risky’ food-seeking strategies in individuals vulnerable to future weight gain. In Experiment 2, prior exposure to a subtle and not easily identifiable food aroma increased selections of the variable delay option following delayed food rewards in a mixed sample of male and female adults, providing preliminary evidence that food cues can sustain uncertain food-seeking strategies. These data highlight a working hypothesis that the rapid delivery and consumption of food rewards, and food cues, can increase risk-tolerance in the food-seeking behaviours of individuals who are vulnerable to weight gain.This article is part of the theme issue ‘Risk taking and impulsive behaviour: fundamental discoveries, theoretical perspectives and clinical implications’.

RATIONALE: Pairing rewarding outcomes with audiovisual cues in simulated gambling games increases risky choice in both humans and rats. However, the cognitive mechanism through which this sensory enhancement biases decision making is unknown. OBJECTIVES: To assess the computational mechanisms that promote risky choice during gambling, we applied a series of reinforcement learning models to a large dataset of choices acquired from rats as they each performed one of two variants of a rat gambling task (rGT), in which rewards on ‘win’ trials were delivered either with or without salient audiovisual cues. METHODS: We used a sampling technique based on Markov Chain Monte Carlo to obtain posterior estimates of model parameters for a series of RL models of increasing complexity, in order to assess the relative contribution of learning about positive and negative outcomes to the latent valuation of each choice option on the cued and uncued rGT. RESULTS: Rats which develop a preference for the risky options on the rGT substantially down-weight the equivalent cost of the time-out punishments during these tasks. For each model tested, the reduction in learning from the negative time-outs correlated with the degree of risk-preference in individual rats. We found no apparent relationship between risk-preference and the parameters that govern learning from the positive rewards. CONCLUSIONS: The emergence of risk-preferring choice on the rGT derives from a relative insensitivity to the cost of the time-out punishments, as opposed to a relative hypersensitivity to rewards. This hyposensitivity to punishment is more likely to be induced in individual rats by the addition of salient audiovisual cues to rewards delivered on win trials.

Our willingness to take risks, our ability to wait or the speed with which to make decisions are central features of our personality. However, it is now recognized that impulsive and risk-taking behaviours are not a unitary construct, and different aspects can be both psychologically and neurally dissociated. The range of neurochemicals and brain systems that govern these behaviours is extensive, and this may be a contributing factor to the phenotypic range seen in the human population. However, this variety can also be pathological as extremes in risk-taking and impulsive behaviours are characteristics of many neuropsychiatric and indeed neurodegenerative disorders. This spans obsessive–compulsive disorder, where behaviour becomes ridged and non-spontaneous, to the nonsensical risk-taking seen in gambling and drug taking. This article is part of the theme issue ‘Risk taking and impulsive behaviour: fundamental discoveries, theoretical perspectives and clinical implications'.

Gambling is a heterogeneous and complex disorder that is phenomenologically similar to drug or alcohol addiction. The range of gambling games continues to proliferate, and the ease of access to gambling opportunities continues to increase. However, there are currently no dedicated pharmacological treatments available for gambling disorder (GD), and the understanding of the neurobiological mechanisms underlying GD is limited. Consequently, GD is increasingly recognised as a significant public health concern. Animal models may facilitate a better understanding of the neurobiological basis of GD. However, gambling is a heterogeneous disorder and may perhaps be better understood by animal paradigms aimed at modeling singular domains of dysfunction observed within human gamblers. These domains include excessive cognitive biases or beliefs, increased impulsivity, deficits in cost-benefit decision-making and augmented cue reactivity. Thus, deficits within one of these core areas could be argued to represent a precipitating vulnerability towards the development of GD. Ergo animal models that can parametrise similar deficits could be used to elucidate the neural and neurochemical systems contributing to these perturbations and may be of considerable benefit in clarifying the pathogenesis of GD. Moreover, such information could be useful in aiding the development of novel pharmacotherapies. Here, we discuss examples of animal research in each of these core domains. Initially we present data from the rodent slot machine task that suggests rats, like humans, are susceptible to the near-miss effect, a potent cognitive distortion that has been linked to the severity of GD. Secondly, we discuss several behavioural tasks designed to capture different aspects of impulsivity in rodents. We then consider tasks that measure distorted or nonoptimal decision-making, before reviewing tasks that measure augmented cue reactivity.

Whilst dopamine agonist therapies can successfully manage the symptoms of diseases such as Parkinson’s disease (PD), fibromyalgia and restless leg syndrome, they can also cause impulse control and addiction disorders such as gambling disorder (GD). These compulsive behaviours seriously undermine the utility of such treatments. The objective of the study was to model this phenomenon using a rodent slot machine task (rSMT) in order to investigate the neurobiological basis underlying such behavioural changes. Male Long Evans rats were trained to perform the rSMT. The D2-like agonist ropinirole, or saline, was then delivered continuously for 28 days via osmotic mini-pump. The effects of ropinirole on baseline rSMT performance, as well as extinction and reinstatement sessions, were determined during this time. Brain samples from key frontostriatal regions implicated in GD and PD were then harvested immediately or after a 4-week washout period during which behaviour returned to pre-drug baseline. Ropinirole invigorated task performance, in that drug treatment resulted in a robust and sustained increase in the number of trials completed. Ex vivo analyses revealed that chronic ropinirole treatment led to a pattern of changes indicative of upregulation within the β-arrestin-AKT-GSK3β intracellular cascade, recently theorised to dominate D2-mediated signalling under hyperdopaminergic conditions, in the dorsal striatum, rather than the canonical PKA-dependent signalling pathway associated with D2 receptor activation. Such findings provide novel insight into the role of dopamine signalling in mediating compulsive-like gambling behaviour and may inform more directed pharmacotherapies for the treatment of both idiopathic and iatrogenic GD.

The power of drug-associated cues to instigate drug 'wanting' and consequently promote drug seeking is a corner stone of contemporary theories of addiction. Gambling disorder has recently been added to the pantheon of addictive disorders due to the phenomenological similarities between the diseases. However, the neurobiological mechanism that may mediate increased sensitivity towards conditioned stimuli in addictive disorders is unclear. We have previously demonstrated using a rodent analogue of a simple slot machine that the dopamine D4 receptor is critically engaged in controlling animals' attribution of salience to stimuli associated with reward in this paradigm, and consequently may represent a target for the treatment of gambling disorder. Here, we investigated the role of acute administration of a D4 receptor agonist on animals' responsivity to conditioned stimuli on both a Pavlovian conditioned approach (autoshaping) and a conditioned reinforcement paradigm. Following training on one of the two tasks, separate cohorts of rats (male and female) were administered a dose of PD168077 shown to be maximally effective at precipitating errors in reward expectancy on the rat slot machine task (10mg/kg). However, augmenting the activity of the D4 receptors in this manner did not alter behaviour on either task. These data therefore provide novel evidence that the D4 receptor does not alter incentive motivation in response to cues on simple behavioural tasks.

D2/3 receptor agonists are effective treatments for Parkinson's disease (PD), but can precipitate impulse control disorders (ICDs) including gambling disorder (GD). The neurobiological mechanisms underlying this devastating side-effect of dopamine agonist replacement therapy (DRT), and any dependence on the dopamine depletion caused by PD, are unclear. It is also unclear whether previous biases towards risk or uncertainty are a risk factor for developing these ICDs. We investigated whether chronic D2/3 agonist administration (5 mg/kg/day ropinirole for 28 days) altered performance of a rat model of gambling-like behaviour, the rodent betting task (rBT), and examined if baseline behaviour predicted this behavioural change. The rBT captures individual differences in subjective preference for uncertain outcomes: animals choose between guaranteed or probabilistic reinforcement of equal expected value. Chronic ropinirole dramatically increased selection of the uncertain option in two-thirds of animals, regardless of baseline preferences. The effect on choice in the rBT was replicated in a dorsolateral striatal 6-hydroxydopamine (6-OHDA) rat model of early PD. These studies are the first to look at individual differences in response to chronic, rather than pulsatile, dosing of DRT in a rodent model of gambling behaviour. These findings suggest that DRT-induced PG may stem from increases in subjective valuation of uncertainty. Such symptoms likely arise because of changes in dopaminergic striatal signalling caused by DRT rather than from an interaction between pre-morbid behaviours or PD itself.

In addition to the symptoms of inattention, hyperactivity, and impulsivity, individuals with attention deficit hyperactivity disorder exhibit impaired performance on tests of real-world cost/benefit decision-making. Atomoxetine, a nonstimulant drug approved for the treatment of attention deficit hyperactivity disorder, is a selective norepinephrine reuptake inhibitor administered chronically during adolescence, a time during which the frontal brain regions necessary for executive function undergo extensive maturation. This treatment protocol can affect behavior well into adulthood, but whether it produces long-term changes in complex decision-making has not been investigated. Twenty-four Long-Evans rats were administered saline or 1.0 mg/kg atomoxetine daily from postnatal day 40 to 54. Two weeks after treatment, the adult rats were trained and assessed on the rodent gambling task, in which the animals chose from four options varying in reward, punishment, and uncertainty. Impulsive action was also measured by recording the number of premature responses made. Regardless of the treatment administered during adolescence, rats learned to favor the advantageous options characterized by small, low-penalty rewards in lieu of the larger, higher-penalty reward options. Rodent gambling task performance was then assessed following acute treatment with atomoxetine (0.1-1.0 mg/kg) and amphetamine (0.3-1.5 mg/kg). Across groups, the highest dose of atomoxetine impaired decision-making and decreased premature responding at all doses tested. Amphetamine also impaired choice performance, but selectively increased impulsive action in rats that had previously received atomoxetine treatment during adolescence. These findings contribute to our understanding of the long-term effects associated with chronic adolescent atomoxetine exposure and suggest that this treatment does not alter decision-making under conditions of risk and uncertainty in adulthood.

Although exposure to delta-9-tetrahydrocannabinol (THC) is perceived to be relatively harmless, mounting evidence has begun to show that it is associated with a variety of cognitive deficits, including poor decision making. THC-induced impairments in decision making are thought to be the result of cannabinoid CB1 receptor activation, and although clinical literature suggests that chronic activation via THC contributes to perturbations in decision making, acute CB1 receptor modulation has yielded mixed results. Using an animal model to examine how CB1-specific ligands impact choice biases would provide significant insight as to how recruitment of the endocannabinoid system may influence decision making. Here, we used the rat gambling task (rGT), a validated analogue of the human Iowa Gambling Task, to assess baseline decision making preferences in male Wistar rats. After acquisition rGT performance was measured. Animals were challenged with the CB1 receptor antagonist rimonabant, the partial agonist THC, and the synthetic agonist WIN55,212-2. Animals were also treated acutely with the fatty acid amide hydrolase (FAAH) inhibitor URB597 to selectively upregulate the endocannabinoid anandamide. Blockade of the CB1 receptor produced a trend improvement in decision making in animals who preferred the advantageous task options, yet left choice unaffected in risk-prone rats. Neither CB1 receptor agonist had strong effects on decision making, but a high dose THC decreased premature responses, whereas WIN55,212-2 did the opposite. URB597 did not affect task performance. These results indicate that although chronic CB1 receptor activation may be associated with impaired decision making, acute modulation has modest effects on choice and instead may play a substantive role in regulating impulsive responding.

Cognitive effort is a ubiquitous process, yet surprisingly little is known about the brain mechanisms responsible for evaluating it. Here, we utilize the rat Cognitive Effort Task (rCET) to probe the striatum's role in deciding between options that vary in the amount of cognitive effort required for success. In the rCET, animals choose to perform either an easy trial, in which the attentional demand is low but the potential reward is small, or a difficult trial which is more attentionally demanding but can yield twice the sugar pellets. Twenty-six male Long Evans rats were trained on the rCET and the effects of pharmacologically inactivating the dorsomedial striatum (DMS) and core region of the nucleus accumbens were determined. Temporary inactivation of the DMS decreased all animals' choice of the high-effort, high-reward option, impaired attentional accuracy, and robustly increased premature responding without impairing general indices of motor ability. The DMS therefore appears necessary for the integration of cognitive signals required for optimal performance. In stark contrast, following temporary inactivation of the ventral striatum, subjects were fundamentally unable to perform the task, as reflected by a drastic decrease in the number of trials initiated and an increase in omitted responses. Together, these data suggest the striatum is likely part of a larger cortico-limbic-striatal network whose function is to optimize decisions requiring cognitive effort costs, at least in the attentional domain, and that striatal subregions have dissociable roles in the adjudication and application of this form of cognitive effort.

The parallels between gambling and substance addiction are increasingly acknowledged; despite this, legislation surrounding gambling is being progressively relaxed and opportunities to gamble continue to increase. There are currently no dedicated treatment options for gambling disorder, and as such, it may come to represent a considerable public health concern. Gamblers represent a heterogeneous population; yet, deficits have been repeatedly observed in regard to impulse control and decision making. Additionally, gamblers typically demonstrate greater endorsement of irrational or distorted beliefs regarding gambling in comparison to healthy controls. In this review, we suggest that animal models may offer a valuable opportunity to elucidate the neurobiological basis underlying these three major areas of dysfunction. We present a number of rodent behavioural paradigms that indicate a somewhat common involvement of the dopamine D2-like receptor family. Yet, importantly, these tasks show that these behaviours appear to be both pharmacologically and neurologically dissociable. Use of these animal models could therefore theoretically inform more symptom-directed pharmacotherapies based on areas of dysfunction seen in individuals.

Substance-related and addictive disorders, in particular gambling disorder, are known to be associated with risky decision-making behavior. Several neuroimaging studies have identified the involvement of the insular cortex in decision-making under risk. However, the extent of this involvement remains unclear and the specific contributions of two distinct insular subregions, the rostral agranular (RAIC) and the caudal granular (CGIC), have yet to be examined. Animals were trained to perform a rat gambling task (rGT), in which subjects chose between four options that differed in the magnitude and probability of rewards and penalties. In order to address the roles of the RAIC and CGIC in established choice behavior, pharmacological inactivations of these two subregions via local infusions of GABA receptor agonists were performed following 30 rGT training sessions. The contribution made by the RAIC or CGIC to the acquisition of choice behavior was also determined by lesioning these areas before behavioral training. Inactivation of the RAIC, but not of the CGIC, shifted rats' preference toward options with greater reward frequency and lower punishment. Before rGT acquisition, lesions of the RAIC, but not the CGIC, likewise resulted in a higher preference for options with greater reward frequency and lower punishment, and this persisted throughout the 30 training sessions. Our results provide confirmation of the involvement of the RAIC in rGT choice behavior and suggest that the RAIC may mediate detrimental risky decision-making behavior, such as that associated with addiction and gambling disorder.