Risperidone is an atypical antipsychotic that exerts widespread effects on cognitive functioning. Antipsychotics are most often administered to individuals with schizophrenia, providing relief from positive symptoms primarily through antagonism of the D2 dopamine receptor. One behavior that is often abnormal in schizophrenia and is partially mediated by the D2 receptor is risky decision-making. Therefore, it is critical to understand how antipsychotics impact risky decision-making in healthy subjects to disentangle the influence of schizophrenia and antipsychotics. Here, the effects of risperidone were examined in rats trained in the Risky Decision-making Task (RDT), in which subjects choose between a small, safe reward and a large reward accompanied by escalating risk of mild footshock. Both daily and acute administration of low to medium doses of risperidone induced a female- specific decrease in choice of options associated that had previously been associated with risk, even when the risk was not present. High-dose risperidone reduced risky choice in both sexes, which likely reflected risk aversion in males and cognitive or motivational disruption in females. Moreover, daily risperidone caused a stark reduction in total trials completed and weight in female but not male rats. Shock threshold testing revealed that risperidone-driven avoidance of risky options was unrelated to altered shock sensitivity, but reduced responding on a progressive ratio schedule suggested that risperidone may reduce risky choice by attenuating appetitive motivation. These findings align with emerging evidence of increased sensitivity to cognitive effects of antipsychotics in females.

Risperidone is an atypical antipsychotic that exerts widespread effects on cognitive functioning. Antipsychotics are most often administered to individuals with schizophrenia, providing relief from positive symptoms primarily through antagonism of the D2 dopamine receptor. One behavior that is often abnormal in schizophrenia and is partially mediated by the D2 receptor is risky decision-making. Therefore, it is critical to understand how antipsychotics impact risky decision-making in healthy subjects to disentangle the influence of schizophrenia and antipsychotics. Here, the effects of risperidone were examined in rats trained in the Risky Decision-making Task (RDT), in which subjects choose between a small, safe reward and a large reward accompanied by escalating risk of mild footshock. Both daily and acute administration of low to medium doses of risperidone induced a female-specific decrease in risky decision-making, with high-dose risperidone reducing risky choice in both sexes. Moreover, daily risperidone caused a stark reduction in total trials completed and weight in female but not male rats. Shock threshold testing revealed that risperidone-driven avoidance of risky options was unrelated to altered shock sensitivity, but reduced responding on a progressive ratio schedule suggested that risperidone may reduce risky choice by attenuating appetitive motivation. These findings align with emerging evidence of increased sensitivity to cognitive effects of antipsychotics in females.

Early life adversity (ELA) is associated with a multitude of neural and behavioral aberrations. To develop treatments to mitigate the effects of ELA, it is critical to determine which aspects of cognition are affected and when these disturbances manifest across the lifespan. Here, we tested the effects of maternal separation, an established rodent model of ELA, on punishment-driven risky decision-making longitudinally in both adolescence (25-55 days old) and adulthood (80-100 days old). Risk-taking was assessed with the Risky Decision-making Task, wherein rats choose between a small, safe reward and a large reward accompanied by an escalating risk of punishment (foot shock). We observed that rats exposed to maternal separation were more prone to risk-taking than controls during adolescence, and demonstrated reduced latency to make both risky and safe decisions. Interestingly, this augmented risk-taking was no longer evident in adulthood. Males and females displayed comparable levels of risk-taking during adolescence then diverged in adulthood, with adult males displaying a sharp increase in risk-taking. Finally, we observed that risk-taking changed across the lifespan in rats exposed to maternal separation, but not in control rats. Collectively, these data reveal that ELA engenders risk-taking in adolescence but not adulthood, and that sex differences in risky decision-making are not evident until adulthood. This has important implications for the development of both behavioral and biological treatments to improve decision-making during the vulnerable adolescent period.

Adaptive decision-making requires consideration of risks and rewards associated with each option, as well as subjective preference for risky/safe alternatives. The lateral orbitofrontal cortex (lOFC) contributes to both reward and punishment processing as well as cost/benefit decision-making, but its role in punishment-driven risky decision-making remains unclear. To address this, we trained male rats in the Risky Decision-making Task, wherein subjects chose between a small, safe reward and a large reward with either 0% or 50% risk of foot shock punishment. We then recorded single unit activity in LOFC during task performance to determine how LOFC activity signals risky vs. safe options and choices. We observed that lOFC activity encodes risk in the environment prior to decision-making, then encodes reward magnitude independent of risk during action selection. Machine learning models revealed that lOFC activity accurately predicts risk but less effectively predicts impending choice, although integrating the outcome of the previous trial improved the accuracy of choice prediction. Finally, risk-preferring subjects demonstrated reduced encoding of risk and increased encoding of reward magnitude. This suggests that lOFC serves as a central hub wherein environmental information about risk and reward converges with internal, subjective information to guide risky decision-making.

Effective decision-making involves careful consideration of all rewarding and aversive outcomes. Importantly, negative outcomes often occur later in time, leading to underestimation, or “discounting,” of these consequences. Despite the frequent occurrence of delayed outcomes, little is known about the neurobiology underlying sensitivity to delayed punishment during decision-making. The Delayed Punishment Decision-making Task (DPDT) addresses this by assessing sensitivity to delayed versus immediate punishment in rats. Rats initially avoid punished reinforcers, then select this option more frequently when delay precedes punishment. We used DPDT to examine effects of acute systemic administration of catecholaminergic drugs on sensitivity to delayed punishment in male and female adult rats. Cocaine did not affect choice of rewards with immediate punishment but caused a dose-dependent reduction in choice of delayed punishment. Neither activation nor blockade of D1-like dopamine receptor affected decision-making, but activation of D2-like dopamine receptors reduced choice of delayed punishment. D2 blockade did not attenuate cocaine’s effects on decision-making, suggesting that cocaine’s effects are not dependent on D2 receptor activation. Increasing synaptic norepinephrine via atomoxetine also reduced choice of delayed (but not immediate) punishment. Notably, when DPDT was modified from ascending to descending pre-punishment delays, these drugs did not affect choice of delayed or immediate punishment, although high-dose quinpirole impaired behavioral flexibility. In summary, sensitivity to delayed punishment is regulated by both dopamine and norepinephrine transmission in task-specific fashion. Understanding the neurochemical modulation of decision-making with delayed punishment is a critical step toward treating disorders characterized by aberrant sensitivity to negative consequences.

Substance use disorder (SUD) is associated with a cluster of cognitive disturbances that engender vulnerability to ongoing drug seeking and relapse. Two of these endophenotypes—risky decision-making and impulsivity—are amplified in individuals with substance use disorder and are augmented by repeated exposure to illicit drugs. Identifying genetic factors underlying variability in these traits is critical for early identification, prevention, and treatment of SUD-vulnerable individuals. Here, we compared risky decision-making and different facets of impulsivity between two fully inbred substrains of Lewis rats—LEW/NCrl and LEW/NHsd. We performed whole genome sequencing of both substrain to identify almost all relevant variants. We observed substantial differences in risky decision-making and impulsive behaviors. Relative to LEW/HHsd, the LEW/NCrl substrain accepts higher risk options in a decision-making task and higher rates of premature responses in the differential reinforcement of low rates of responding (DRL) task. These phenotypic differences were more pronounced in females than males. We defined a total of ∼9,000 polymorphisms between these substrains at 40X whole genome short-read coverage. Roughly half of variants are located within a single 1.5 Mb region of chromosome 8, but none impact protein-coding regions. In contrast, other variants are widely distributed, and of these 38 are predicted to cause protein-coding variants. In conclusion, Lewis rat substrains differ significantly in risk-taking and impulsivity and only a small number of easily mapped variants are likely to be causal. Sequencing combined with a reduced complexity cross (RCC) should enable identification of one or more variants underlying multiple complex addiction-relevant traits.

Cannabis exerts an indirect effect on dopamine (DA) output in the mesolimbic projection, a circuit implicated in reward processing and effort expenditure, and thus may be associated with aberrant effort-based decision making. The "amotivation syndrome" hypothesis suggests that regular cannabis use results in impaired capacity for goal-directed behavior. However, investigations of this hypothesis have used divergent methodology and have not controlled for key confounding variables. The present study extends these findings by examining the relation between cannabis use and effort-related decision making in a sample of college students. Cannabis using (n = 25; 68% meeting criteria for Cannabis Use Disorder) and noncannabis using (n = 22) students completed the Effort Expenditure for Rewards Task (EEfRT). In generalized estimating equation models, reward magnitude, reward probability, and expected value predicted greater likelihood of selecting a high-effort trial. Furthermore, past-month cannabis days and cannabis use disorder symptoms predicted the likelihood of selecting a high-effort trial, such that greater levels of both cannabis use days and symptoms were associated with an increased likelihood after controlling for Attention Deficit/Hyperactivity Disorder (ADHD) symptoms, distress tolerance, income, and delay discounting. The results provide preliminary evidence suggesting that college students who use cannabis are more likely to expend effort to obtain reward, even after controlling for the magnitude of the reward and the probability of reward receipt. Thus, these results do not support the amotivational syndrome hypothesis. Future research with a larger sample is required to evaluate possible associations between cannabis use and patterns of real-world effortful behavior over time. Public Health Significance Cannabis use is becoming increasingly tolerated, both culturally and legally; yet, the risks associated with cannabis use are still unclear. There is a perception among the general public that cannabis leads to amotivation and diminished effortful behavior. Our results do not support the amotivational hypothesis but, instead, that cannabis use is associated with a greater likelihood of selecting high effort trials.

Epigallocatechin-3-gallate (EGCG) and caffeine are the two primary compounds found in green tea. While EGCG has anxiolytic and anti-inflammatory effects, its acute effects on cognition are not well understood. Furthermore, despite widespread green tea consumption, little is known about how EGCG and caffeine co-administration impacts behavior. Here, we investigated the effects of multiple doses of either EGCG or caffeine on a rat model of risk-taking. This was assessed using the risky decision-making task (RDT), in which rats choose between a small, well-tolerated reward and a large reward with escalating risk of mild footshock. Rats were tested in RDT after acute systemic administration of EGCG, caffeine or joint EGCG and caffeine. EGCG caused a dose-dependent reduction in risk-taking without affecting reward discrimination or task engagement. Caffeine did not impact risk-taking, but elevated locomotor activity and reduced task engagement at high doses. Finally, exposure to both EGCG and caffeine had no effect on risk-taking, suggesting that low-dose caffeine is sufficient to mask the risk-aversion caused by EGCG. These data suggest EGCG as a potential therapeutic treatment for psychological disorders that induce compulsive risky decision-making.

While the cognitive enhancing effects of nicotine use have been well documented, it has also been shown to impair decision making. The goal of this study was to determine if exposure to nicotine vapor increases risky decision making. The study also aims to investigate possible long-term effects of nicotine vapor exposure on the expression of genes coding for cholinergic and dopaminergic receptors in brain. Thirty-two adult male Sprague Dawley rats were exposed to 24 mg/mL nicotine vapor or vehicle control, immediately followed by testing in the probability discounting task for 10 consecutive days. Fifty-four days after the 10-day vapor exposure, animals were sacrificed and expression of genes coding for the α4 and β2 cholinergic receptor subunits, and dopamine D1 and D2 receptors, were analyzed using RT-PCR. Exposure to nicotine vapor caused an immediate and transient increase in risky choice. Analyses of gene expression identified significant reductions in CHRNB2 and DRD1 in the nucleus accumbens core and CHRNB2 and DRD2 in the medial prefrontal cortex of rats previously exposed to nicotine vapor, relative to vehicle controls. Results provide data on the negative cognitive effects of nicotine vapor exposure and identify cholinergic and dopaminergic mechanisms that may affected with repeated use.

In real-world decision-making scenarios, negative consequences do not always occur immediately after a choice. This delay between action and outcome drives the underestimation, or "delay discounting," of punish-ment. While the neural substrates underlying sensitivity to immediate punishment have been well-studied, there has been minimal investigation of delayed consequences. Here, we assessed the role of lateral orbito-frontal cortex (LOFC) and basolateral amygdala (BLA), two regions implicated in cost/benefit decision-making, in sensitivity to delayed versus immediate punishment. The delayed punishment decision-making task (DPDT) was used to measure delay discounting of punishment in rodents. During DPDT, rats choose between a small, single-pellet reward and a large, three-pellet reward accompanied by a mild foot shock. As the task pro-gresses, the shock is preceded by a delay that systematically increases or decreases throughout the session. We observed that rats avoid choices associated with immediate punishment, then shift preference toward these options when punishment is delayed. LOFC inactivation did not influence choice of rewards with imme-diate punishment, but decreased choice of delayed punishment. We also observed that BLA inactivation re-duced choice of delayed punishment for ascending but not descending delays. Inactivation of either brain region produced comparable effects on decision-making in males and females, but there were sex differences observed in omissions and latency to make a choice. In summary, both LOFC and BLA contribute to the delay discounting of punishment and may serve as promising therapeutic targets to improve sensitivity to delayed punishment during decision-making.

Epigallocatechin-3-gallate (EGCG) and caffeine are the two primary compounds found in green tea. While EGCG has anxiolytic and anti-inflammatory effects, its acute effects on cognition are not well understood. Furthermore, despite widespread green tea consumption, little is known about how EGCG and caffeine co-administration impact behavior. Here, we investigated the effects of multiple doses of either EGCG or caffeine on a rat model of risk-taking. This was assessed using the risky decision-making task (RDT), in which rats choose between a small, safe reward and a large reward with escalating risk of mild footshock. Rats were tested in RDT after acute systemic administration of EGCG, caffeine, or joint EGCG and caffeine. EGCG caused a dose dependent reduction in risk-taking without affecting reward discrimination or task engagement. Caffeine did not impact risk taking, but elevated locomotor activity and reduced task engagement at high doses. Finally, exposure to both EGCG and caffeine had no effect on risk-taking, suggesting that low-dose caffeine is sufficient to mask the risk-aversion caused by EGCG. These data suggest EGCG as a potential therapeutic treatment for psychological disorders that induce compulsive risky decision-making.

RATIONALE:Optimal decision-making necessitates evaluation of multiple rewards that are each offset by distinct costs, such as high effort requirement or high risk of failure. The neurotransmitter dopamine is fundamental toward these cost-benefit analyses, and D1-like and D2-like dopamine receptors differently modulate the reward-discounting effects of both effort and risk. However, measuring the role of dopamine in regulating decision-making between options associated with distinct costs exceeds the scope of traditional rodent economic decision-making paradigms.OBJECTIVES:We developed the effort vs probability economic conflict task (EvP) to model multimodal economic decision-making in rats. This task measures choice between two rewards of uniform magnitude associated with either a high effort requirement or risk of reward omission. We then tested the modulatory effects of systemic cocaine and D1/D2 blockade or activation on the preference between high-effort and high-risk alternatives.METHODS:In the EvP, two reinforcers of equal magnitude are associated with either (1) an effort requirement that increases throughout the session (1, 5, 10, and 20 lever presses), or (2) a low probability of reward receipt (25% of probabilistic choices). Critically, the reinforcer for each choice is comparable (one pellet), which eliminates the influence of magnitude discrimination on the decision-making process. After establishing the task, the dopamine transporter blocker cocaine and D1/D2 antagonists and agonists were administered prior to EvP performance.RESULTS:Preference shifted away from either effortful or probabilistic choice when either option became more costly, and this preference was highly variable between subjects and stable over time. Cocaine, D1 activation, and D2 blockade produced limited, dose-dependent shifts in choice preference contingent on high or low effort conditions. In contrast, D2 activation across multiple doses evoked a robust shift from effortful to risky choice that was evident even when clearly disadvantageous.CONCLUSIONS:The EvP clearly demonstrates that rats can evaluate distinct effortful or risky costs associated with rewards of comparable magnitude, and shift preference away from either option with increasing cost. This preference is more tightly linked to D2 than D1 receptor manipulation, suggesting D2-like receptors as a possible therapeutic target for maladaptive biases toward risk-taking over effort.

Recent changes in policy regarding cannabis in the U.S. have been accompanied by an increase in the prevalence of cannabis use and a reduction in the perceived harms associated with consumption. However, little is understood regarding the effects of cannabinoids on cognitive processes. Given that deficient risk-taking is commonly observed in individuals suffering from substance use disorders (SUDs), we assessed the impact of manipulating cannabinoid type 1 receptors (CBRs; the primary target for Δ-tetrahydrocannabinol in the brain) on punishment-based risk-taking using the risky decision-making task (RDT) in male Long-Evans rats. The RDT measures preference for small, safe rewards over large, risky rewards associated with an escalating chance of foot shock. Systemic bidirectional CBR manipulation with a CBR agonist, CBR antagonist, and FAAH inhibitor (which increases overall endocannabinoid tone) did not alter overt risk-taking in the RDT. Interestingly, direct CBR agonism, but not indirect CBR stimulation or CBR blockade, resulted in reduction in latency to make risky choices while not altering safe choice latency. Our findings suggest that CBR activation expedites engagement in punishment based risk-taking without affecting overall preference for risky vs. safe options. This indicates that risk preference and rate of deliberation for risk-taking are influenced by distinct neural substrates, an important consideration for development of precise treatments targeting the aberrant risk-taking typical of SUD symptomology.

Deficits in decision making are at the heart of many psychiatric diseases, such as substance abuse disorders and attention deficit hyperactivity disorder. Consequently, rodent models of decision making are germane to understanding the neural mechanisms underlying adaptive choice behavior and how such mechanisms can become compromised in pathological conditions. A critical factor that must be integrated with reward value to ensure optimal decision making is the occurrence of consequences, which can differ based on probability (risk of punishment) and temporal contiguity (delayed punishment). This article will focus on two models of decision making that involve explicit punishment, both of which recapitulate different aspects of consequences during human decision making. We will discuss each behavioral protocol, the parameters to consider when designing an experiment, and finally how such animal models can be utilized in studies of psychiatric disease. © 2020 Wiley Periodicals LLC. Basic Protocol 1: Behavioral training Support Protocol: Equipment testing Alternate Protocol: Reward discrimination Basic Protocol 2: Risky decision-making task (RDT) Basic Protocol 3: Delayed punishment decision-making task (DPDT).

Differences in the prevalence and presentation of psychiatric illnesses in men and women suggest that neurobiological sex differences confer vulnerability or resilience in these disorders. Rodent behavioral models are critical for understanding the mechanisms of these differences. Reward processing and punishment avoidance are fundamental dimensions of the symptoms of psychiatric disorders. Here we explored sex differences along these dimensions using multiple and distinct behavioral paradigms. We found no sex difference in reward-guided associative learning but a faster punishment-avoidance learning in females. After learning, females were more sensitive than males to probabilistic punishment but less sensitive when punishment could be avoided with certainty. No sex differences were found in reward-guided cognitive flexibility. Thus, sex differences in goal-directed behaviors emerged selectively when there was an aversive context. These differences were critically sensitive to whether the punishment was certain or unpredictable. Our findings with these new paradigms provide conceptual and practical tools for investigating brain mechanisms that account for sex differences in susceptibility to anxiety and impulsivity. They may also provide insight for understanding the evolution of sex-specific optimal behavioral strategies in dynamic environments.

Excessive preference for risky over safe options is a hallmark of several psychiatric disorders. Here we describe a behavioral task that models such risky decision making in rats. In this task, rats are given choices between small, safe rewards and large rewards accompanied by risk of footshock punishment. The risk of punishment changes within a test session, allowing quantification of decision making at different levels of risk. Importantly, this task can yield a wide degree of reliable individual variability, allowing the characterization of rats as "risk-taking" or "risk-averse." The task has been demonstrated to be effective for testing the effects of pharmacological agents and neurobiological manipulations, and the individual variability (which mimics the human population) allows assessment of behavioral and neurobiological distinctions among subjects based on their risk-taking profile.

The risky decision-making task (RDT) measures risk-taking in a rat model by assessing preference between a small, safe reward and a large reward with increasing risk of punishment (mild foot shock). It is well-established that dopaminergic drugs modulate risk-taking; however, little is known about how differences in baseline phasic dopamine signaling drive individual differences in risk preference. Here, we used in vivo fixed potential amperometry in male Long-Evans rats to test if phasic nucleus accumbens shell (NACs) dopamine dynamics are associated with risk-taking. We observed a positive correlation between medial forebrain bundle-evoked dopamine release in the NACs and risky decision-making, suggesting that risk-taking is associated with elevated dopamine sensitivity. Moreover, "risk-taking" subjects were found to demonstrate greater phasic dopamine release than "risk-averse" subjects. Risky decision-making also predicted enhanced sensitivity to the dopamine reuptake inhibitor nomifensine, and elevated autoreceptor function. Importantly, this hyperdopaminergic phenotype was selective for risky decision-making, as delay discounting performance was not predictive of phasic dopamine release or dopamine supply. These data identify phasic NACs dopamine release as a possible therapeutic target for alleviating the excessive risk-taking observed across multiple forms of psychopathology.