D2/3 Agonist during Learning Potentiates Cued Risky Choice.

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 vivo cFos 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 STATEMENT D2/3 receptor 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.

Dopamine activity in the nigrostriatal pathway alters cue-induced risky choice patterns in female rats.

Deficits in cost/benefit decision making is a critical risk factor for gambling disorder. Reward-paired cues may play an important role, as these stimuli can enhance risk preference in rats. Despite extensive research implicating the dorsal striatum in the compulsive aspects of addiction, the role of nigrostriatal dopaminergic activity in cue-induced risk preference remains unclear, particularly in females. Accordingly, we examined the effects of manipulating the dopaminergic nigrostriatal pathway on cue-induced risky choice in female rats. TH:Cre rats were trained on the cued version of the rat Gambling Task. This task was designed such that maximal reward is attained by avoiding the high-risk, high-reward options and instead favouring the options associated with lower per-trial gains, as they feature less frequent and shorter time-out penalties. Adding reward-paired audiovisual cues to the task leads to greater risky choice on average. To assess the role of the nigrostriatal pathway, a viral vector carrying either Cre-dependent inhibitory or excitatory DREADD was infused into the substantia nigra. Rats then received clozapine-N-oxide either during task acquisition or after a stable performance baseline was reached. Inhibition of this pathway accelerated the development of risk preference in early sessions and increased risky choice during performance, but long-term inhibition actually improved decision making. Activation of this pathway had minimal effects. These results provide evidence for the involvement of the dopaminergic nigrostriatal pathway in cue-induced risk preference in females, therefore shedding light on its role in cost/benefit decision-making deficits and expanding our knowledge of the female dopaminergic system.

Neural Mechanisms Mediating Sex Differences in Motivation for Reward: Cognitive Bias, Food, Gambling, and Drugs of Abuse.

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.

Decreased risk-taking and loss-chasing after subthalamic nucleus lesion in rats.

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.

Evaluation of cognitive effort in rats is not critically dependent on ventrolateral orbitofrontal cortex.

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.

Dopamine neurons gate the intersection of cocaine use, decision making, and impulsivity.

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 likewise 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 changes 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.

Prior Exposure to Salient Win-Paired Cues in a Rat Gambling Task Increases Sensitivity to Cocaine Self-Administration and Suppresses Dopamine Efflux in Nucleus Accumbens: Support for the Reward Deficiency Hypothesis of Addiction.

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.

Decreased motor impulsivity following chronic lithium treatment in male rats is associated with reduced levels of pro-inflammatory cytokines in the orbitofrontal cortex.

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-1ß, IL-10 and RANTES (CCL-5) were reduced in lithium-treated rats at this time point. IL-1ß, 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.

Exposure to uncertainty mediates the effects of traumatic brain injury on probabilistic decision-making in rats.

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 naïve 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.

Win-Concurrent Sensory Cues Can Promote Riskier Choice.

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 STATEMENT Animal 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.

Cocaine self-administration is increased after frontal traumatic brain injury and associated with neuroinflammation.

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 10 6-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.

Investigating the influence of 'losses disguised as wins' on decision making and motivation in rats.

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.

Dopamine D3 Receptors Modulate the Ability of Win-Paired Cues to Increase Risky Choice in a Rat Gambling Task.

Similar to other addiction disorders, the cues inherent in many gambling procedures are thought to play an important role in mediating their addictive nature. Animal models of gambling-related behavior, while capturing dimensions of economic decision making, have yet to address the impact that these salient cues may have in promoting maladaptive choice. Here, we determined whether adding win-associated audiovisual cues to a rat gambling task (rGT) would influence decision making. Thirty-two male Long-Evans rats were tested on either the cued or uncued rGT. In these tasks, animals chose between four options associated with different magnitudes and frequencies of reward and punishing time-out periods. As in the Iowa Gambling Task, favoring options associated with smaller per-trial rewards but smaller losses and avoiding the tempting "high-risk, high-reward" decks maximized profits. Although the reinforcement contingencies were identical in both task versions, rats' choice of the disadvantageous risky options was significantly greater on the cued task. Furthermore, a D3 receptor agonist increased choice of the disadvantageous options, whereas a D3 antagonist had the opposite effects, only on the cued task. These findings are consistent with the reported role of D3 receptors in mediating the facilitatory effects of cues in addiction. Collectively, these results indicate that the cued rGT is a valuable model with which to study the mechanism by which salient cues can invigorate maladaptive decision making, an important and understudied component of both gambling and substance use disorders. Significance statement: We used a rodent analog of the Iowa Gambling Task to determine whether the addition of audiovisual cues would affect choice preferences. Adding reward-concurrent cues significantly increased risky choice. This is the first clear demonstration that reward-paired cues can bias cost/benefit decision making against a subject's best interests in a manner concordant with elevated addiction susceptibility. Choice on the cued task was uniquely sensitive to modulation by D3 receptor ligands, yet these drugs did not alter decision making on the uncued task. The relatively unprecedented sensitivity of choice on the cued task to D3-receptor-mediated neurotransmission data suggest that similar neurobiological processes underlie the ability of cues to both bias animals toward risky options and facilitate drug addiction.

Deciphering Decision Making: Variation in Animal Models of Effort- and Uncertainty-Based Choice Reveals Distinct Neural Circuitries Underlying Core Cognitive Processes.

Maladaptive decision-making is increasingly recognized to play a significant role in numerous psychiatric disorders, such that therapeutics capable of ameliorating core impairments in judgment may be beneficial in a range of patient populations. The field of "decision neuroscience" is therefore in its ascendancy, with researchers from diverse fields bringing their expertise to bear on this complex and fascinating problem. In addition to the advances in neuroimaging and computational neuroscience that contribute enormously to this area, an increase in the complexity and sophistication of behavioral paradigms designed for nonhuman laboratory animals has also had a significant impact on researchers' ability to test the causal nature of hypotheses pertaining to the neural circuitry underlying the choice process. Multiple such decision-making assays have been developed to investigate the neural and neurochemical bases of different types of cost/benefit decisions. However, what may seem like relatively trivial variation in behavioral methodologies can actually result in recruitment of distinct cognitive mechanisms, and alter the neurobiological processes that regulate choice. Here we focus on two areas of particular interest, namely, decisions that involve an assessment of uncertainty or effort, and compare some of the most prominent behavioral paradigms that have been used to investigate these processes in laboratory rodents. We illustrate how an appreciation of the diversity in the nature of these tasks can lead to important insights into the circumstances under which different neural regions make critical contributions to decision making.

Chronic D2/3 agonist ropinirole treatment increases preference for uncertainty in rats regardless of baseline choice patterns.

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.

Δ9-Tetrahydrocannabinol decreases willingness to exert cognitive effort in male rats.

BACKGROUND: Acceptance of cannabis use is growing. However, prolonged use is associated with diminished psychosocial outcomes, potentially mediated by drug-induced cognitive impairments. Δ9-Tetrahydrocannabinol (THC) is the main psychoactive ingredient in cannabis, yet other phytocannabinoids in the plant, such as cannabidiol (CBD), have unique properties. Given that CBD can modulate the undesirable effects of THC, therapeutic agents, such as nabiximols, contain higher CBD:THC ratios than illicit marijuana. We tested the hypothesis that THC impairs a relevant cognitive function for long-term success, namely willingness to exert cognitive effort for greater rewards, and that CBD could attenuate such decision-making impairments. METHODS: Male Long-Evans rats (n = 29) performing the rat cognitive effort task (rCET) received acute THC and CBD, independently and concurrently, in addition to other cannabinoids. Rats chose between 2 options differing in reward magnitude, but also in the cognitive effort (attentional load) required to obtain them. RESULTS: We found that THC decreased choice of hard trials without impairing the animals' ability to accurately complete them. Strikingly, this impairment was correlated with CB1 receptor density in the medial prefrontal cortex - an area previously implicated in effortful decision-making. In contrast, CBD did not affect choice. Coadministration of 1:1 CBD:THC matching that in nabiximols modestly attenuated the deleterious effects of THC in "slacker" rats. LIMITATIONS: Only male rats were investigated, and the THC/CBD coadministration experiment was carried out in a subset of individuals. CONCLUSION: These findings confirm that THC, but not CBD, selectively impairs decision-making involving cognitive effort costs. However, coadministration of CBD only partially ameliorates such THC-induced dysfunction.

Prefrontal Cortical Inactivations Decrease Willingness to Expend Cognitive Effort on a Rodent Cost/Benefit Decision-Making Task.

Personal success often necessitates expending greater effort for greater reward but, equally important, also requires judicious use of our limited cognitive resources (e.g., attention). Previous animal models have shown that the prelimbic (PL) and infralimbic (IL) regions of the prefrontal cortex (PFC) are not involved in (physical) effort-based choice, whereas human studies have demonstrated PFC contributions to (mental) effort. Here, we utilize the rat Cognitive Effort Task (rCET) to probe PFC's role in effort-based decision making. In the rCET, animals can choose either an easy trial, where the attentional demand is low but the reward (sugar) is small or a difficult trial on which both the attentional demand and reward are greater. Temporary inactivation of PL and IL decreased all animals' willingness to expend mental effort and increased animals' distractibility; PL inactivations more substantially affected performance (i.e., attention), whereas IL inactivations increased motor impulsivity. These data imply that the PFC contributes to attentional resources, and when these resources are diminished, animals shift their choice (via other brain regions) accordingly. Thus, one novel therapeutic approach to deficits in effort expenditure may be to focus on the resources that such decision making requires, rather than the decision-making process per se.

Risk-preferring rats make worse decisions and show increased incubation of craving after cocaine self-administration.

Maladaptive decision-making may play an integral role in the development and maintenance of an addiction. Substance-dependent individuals make riskier choices on the Iowa Gambling Task, and these deficits persist during withdrawal and are predictive of relapse. However, it is unclear from clinical studies whether this cognitive impairment is a cause or consequence of drug use. We trained male Long-Evans rats on the rat Gambling Task, a rodent analogue of the Iowa Gambling Task, to determine how choice preference influenced, and was influenced by, cocaine self-administration, withdrawal and incubation of craving. Rats that exhibited a preference for the risky, disadvantageous options at baseline were uniquely and adversely affected by cocaine self-administration. Risky choice was exacerbated in these rats when decision-making was assessed during the same diurnal period as cocaine self-administration, whereas the choice pattern of optimal decision-makers was unaffected. This decision-making deficit was maintained during 30 days of withdrawal and correlated with greater cue-induced incubation of craving. Risk-preferring rats also made more drug-seeking responses during cocaine self-administration. These data demonstrate that poor decision-making prior to contact with addictive drugs is associated with a pro-addictive behavioural phenotype, characterized by further increased risky choice and heightened responding for drug both during cocaine self-administration and withdrawal. Such findings indicate that the elevated risky decision-making observed in substance-dependent populations is not merely circumstantial, but makes an important contribution to addiction vulnerability and severity that can now be effectively modelled in laboratory rats.

Δ9-Tetrahydrocannabinol decreases willingness to exert cognitive effort in male rats.

BACKGROUND: Acceptance of cannabis use is growing. However, prolonged use is associated with diminished psychosocial outcomes, potentially mediated by drug-induced cognitive impairments. Δ9-Tetrahydrocannabinol (THC) is the main psychoactive ingredient in cannabis, yet other phytocannabinoids in the plant, such as cannabidiol (CBD), have unique properties. Given that CBD can modulate the undesirable effects of THC, therapeutic agents, such as nabiximols, contain higher CBD:THC ratios than illicit marijuana. We tested the hypothesis that THC impairs a relevant cognitive function for long-term success, namely willingness to exert cognitive effort for greater rewards, and that CBD could attenuate such decision-making impairments. METHODS: Male Long-Evans rats (n = 29) performing the rat cognitive effort task (rCET) received acute THC and CBD, independently and concurrently, in addition to other cannabinoids. Rats chose between 2 options differing in reward magnitude, but also in the cognitive effort (attentional load) required to obtain them. RESULTS: We found that THC decreased choice of hard trials without impairing the animals' ability to accurately complete them. Strikingly, this impairment was correlated with CB1 receptor density in the medial prefrontal cortex - an area previously implicated in effortful decision-making. In contrast, CBD did not affect choice. Coadministration of 1:1 CBD:THC matching that in nabiximols modestly attenuated the deleterious effects of THC in "slacker" rats. LIMITATIONS: Only male rats were investigated, and the THC/CBD coadministration experiment was carried out in a subset of individuals. CONCLUSION: These findings confirm that THC, but not CBD, selectively impairs decision-making involving cognitive effort costs. However, coadministration of CBD only partially ameliorates such THC-induced dysfunction.

Chronic atomoxetine treatment during adolescence does not influence decision-making on a rodent gambling task, but does modulate amphetamine's effect on impulsive action in adulthood.

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.