Cocaine intake correlates with risk-taking behavior and affects estrous cycling in female Sprague-Dawley rats.

Navigating complex decisions and considering their relative risks and rewards is an important cognitive ability necessary for survival. However, use of and dependence on illicit drugs can result in long-lasting changes to this risk/reward calculus in individuals with substance use disorder. Recent work has shown that chronic exposure to cocaine causes long-lasting increases in risk taking in male and female rats, but there are still significant gaps in our understanding of the relationship between cocaine use and changes in risk taking. For example, it is unclear whether the magnitude of cocaine intake dictates the extent to which risk taking is altered. To address this, male and female Sprague-Dawley rats underwent cocaine (or sucrose) self-administration and, following a period of abstinence, were trained and tested in a rodent model of risky decision making. In this behavioral task, rats made discrete-trial choices between a lever associated with a small food reward (i.e., "safe" option) and a lever associated with a larger food reward accompanied by a variable risk of footshock delivery (i.e., "risky" option). Surprisingly, and in contrast to prior work in Long-Evans rats, there were no effects of cocaine self-administration on choice of the large, risky reward (i.e., risk taking) during abstinence in males or females. There was, however, a significant relationship between cocaine intake and risk taking in female rats, with greater intake associated with greater preference for the large, risky reward. Relative to their sucrose counterparts, female rats in the cocaine group also exhibited irregular estrous cycles, characterized by prolonged estrus and/or diestrus phases. Collectively, these data suggest that there may be strain differences in the effects of cocaine on risk taking and highlight the impact that chronic cocaine exposure has on hormonal cyclicity in females. Future work will focus on understanding the neural mechanisms underlying cocaine's intake-dependent effects on risk taking in females, and whether this is directly related to cocaine-induced alterations in neuroendocrine function.

Effects of fentanyl self-administration on risk-taking behavior in male rats.

RATIONALE: Individuals with opioid use disorder (OUD) exhibit impaired decision making and elevated risk-taking behavior. In contrast to the effects of natural and semi-synthetic opioids, however, the impact of synthetic opioids on decision making is still unknown. OBJECTIVES: The objective of the current study was to determine how chronic exposure to the synthetic opioid fentanyl alters risk-based decision making in adult male rats. METHODS: Male rats underwent 14 days of intravenous fentanyl or oral sucrose self-administration. After 3 weeks of abstinence, rats were tested in a decision-making task in which they chose between a small, safe food reward and a large food reward accompanied by variable risk of footshock punishment. Following testing in the decision-making task, rats were tested in control assays that assessed willingness to work for food and shock reactivity. Lastly, rats were tested on a probabilistic reversal learning task to evaluate enduring effects of fentanyl on behavioral flexibility. RESULTS: Relative to rats in the sucrose group, rats in the fentanyl group displayed greater choice of the large, risky reward (risk taking), an effect that was present as long as 7 weeks into abstinence. This increased risk taking was driven by enhanced sensitivity to the large rewards and diminished sensitivity to punishment. The fentanyl-induced elevation in risk taking was not accompanied by alterations in food motivation or shock reactivity or impairments in behavioral flexibility. CONCLUSIONS: Results from the current study reveal that the synthetic opioid fentanyl leads to long-lasting increases in risk taking in male rats. Future experiments will extend this work to females and identify neural mechanisms that underlie these drug-induced changes in risk taking.

Circuit and Cell-Specific Contributions to Decision Making Involving Risk of Explicit Punishment in Male and Female Rats.

Decision making is a complex cognitive process that recruits a distributed network of brain regions, including the basolateral amygdala (BLA) and nucleus accumbens shell (NAcSh). Recent work suggests that communication between these structures, as well as activity of cells expressing dopamine (DA) D2 receptors (D2R) in the NAcSh, are necessary for some forms of decision making; however, the contributions of this circuit and cell population during decision making under risk of punishment are unknown. The current experiments addressed this question using circuit-specific and cell type-specific optogenetic approaches in rats during a decision making task involving risk of punishment. In experiment 1, Long-Evans rats received intra-BLA injections of halorhodopsin or mCherry (control) and in experiment 2, D2-Cre transgenic rats received intra-NAcSh injections of Cre-dependent halorhodopsin or mCherry. Optic fibers were implanted in the NAcSh in both experiments. Following training in the decision making task, BLA→NAcSh or D2R-expressing neurons were optogenetically inhibited during different phases of the decision process. Inhibition of the BLA→NAcSh during deliberation (the time between trial initiation and choice) increased preference for the large, risky reward (increased risk taking). Similarly, inhibition during delivery of the large, punished reward increased risk taking, but only in males. Inhibition of D2R-expressing neurons in the NAcSh during deliberation increased risk taking. In contrast, inhibition of these neurons during delivery of the small, safe reward decreased risk taking. These findings extend our knowledge of the neural dynamics of risk taking, revealing sex-dependent circuit recruitment and dissociable activity of selective cell populations during decision making.SIGNIFICANCE STATEMENT Until recently, the ability to dissect the neural substrates of decision making involving risk of punishment (risk taking) in a circuit-specific and cell-specific manner has been limited by the tools available for use in rats. Here, we leveraged the temporal precision of optogenetics, together with transgenic rats, to probe contributions of a specific circuit and cell population to different phases of risk-based decision making. Our findings reveal basolateral amygdala (BLA)→nucleus accumbens shell (NAcSh) is involved in evaluation of punished rewards in a sex-dependent manner. Further, NAcSh D2 receptor (D2R)-expressing neurons make unique contributions to risk taking that vary across the decision making process. These findings advance our understanding of the neural principles of decision making and provide insight into how risk taking may become compromised in neuropsychiatric diseases.

Circuit and cell-specific contributions to decision making involving risk of explicit punishment in male and female rats.

Decision making is a complex cognitive process that recruits a distributed network of brain regions, including the basolateral amygdala (BLA) and nucleus accumbens shell (NAcSh). Recent work suggests that communication between these structures, as well as activity of cells expressing dopamine D2 receptors (D2R) in the NAcSh, are necessary for some forms of decision making; however, the contributions of this circuit and cell population during decision making under risk of punishment are unknown. The current experiments addressed this question using circuit- and cell type-specific optogenetic approaches in rats during a decision-making task involving risk of punishment. In Experiment 1, Long-Evans rats received intra-BLA injections of halorhodopsin or mCherry (control) and in Experiment 2, D2-Cre transgenic rats received intra-NAcSh injections of Cre-dependent halorhodopsin or mCherry. Optic fibers were implanted in the NAcSh in both experiments. Following training in the decision-making task, BLA→NAcSh or D2R-expressing neurons were optogenetically inhibited during different phases of the decision process. Inhibition of the BLA→NAcSh during deliberation (the time between trial initiation and choice) increased choice of the large, risky reward (increased risk taking). Similarly, inhibition during delivery of the large, punished reward increased risk taking, but only in males. Inhibition of D2R-expressing neurons in the NAcSh during deliberation increased risk taking. In contrast, inhibition of these neurons during delivery of the small, safe reward decreased risk taking. These findings extend our knowledge of the neural dynamics of risk taking, revealing sex-dependent circuit recruitment and dissociable activity of selective cell populations during decision making.

Age-Related Changes in Risky Decision Making and Associated Neural Circuitry in a Rat Model.

Altered decision making at advanced ages can have a significant impact on an individual's quality of life and the ability to maintain personal independence. Relative to young adults, older adults make less impulsive and less risky choices; although these changes in decision making could be considered beneficial, they can also lead to choices with potentially negative consequences (e.g., avoidance of medical procedures). Rodent models of decision making have been invaluable for dissecting cognitive and neurobiological mechanisms that contribute to age-related changes in decision making, but they have predominantly used costs related to timing or probability of reward delivery and have not considered other equally important costs, such as the risk of adverse consequences. The current study therefore used a rat model of decision making involving risk of explicit punishment to examine age-related changes in this form of choice behavior in male rats, and to identify potential cognitive and neurobiological mechanisms that contribute to these changes. Relative to young rats, aged rats displayed greater risk aversion, which was not attributable to reduced motivation for food, changes in shock sensitivity, or impaired cognitive flexibility. Functional MRI analyses revealed that, overall, functional connectivity was greater in aged rats compared with young rats, particularly among brain regions implicated in risky decision making such as basolateral amygdala, orbitofrontal cortex, and ventral tegmental area. Collectively, these findings are consistent with greater risk aversion found in older humans, and reveal age-related changes in brain connectivity.

Cognitive mechanisms underlying decision making involving risk of explicit punishment in male and female rats.

Individuals engage in the process of risk-based decision making on a daily basis to navigate various aspects of life. There are, however, individual differences in this form of decision making, with some individuals exhibiting preference for riskier choices (risk taking) and others exhibiting preference for safer choices (risk aversion). Recent work has shown that extremes in risk taking (e.g., excessive risk taking or risk aversion) are not only cognitive features of neuropsychiatric diseases, but may in fact predispose individuals to the development of such diseases. To better understand individual differences in risk taking, and thus the mechanisms by which they confer disease vulnerability, the current study investigated the cognitive contributions to risk taking in both males and females. Rats were first behaviorally characterized in a decision-making task involving risk of footshock punishment and then tested on a battery of cognitive behavioral assays. Individual variability in risk taking was compared with performance on these tasks. Consistent with prior work, females were more risk averse than males. With the exception of the Set-shifting Task, there were no sex differences in performance on other cognitive assays. There were, however, sex-dependent associations between risk taking and specific cognitive measures. Greater risk taking was associated with better cognitive flexibility in males whereas greater risk aversion was associated with better working memory in females. Collectively, these findings reveal that distinct cognitive mechanisms are associated with risk taking in males and females, which may account for sex differences in this form of decision making.

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.

Regulation of sex differences in risk-based decision making by gonadal hormones: Insights from rodent models.

Men and women differ in their ability to evaluate options that vary in their rewards and the risks that are associated with these outcomes. Most studies have shown that women are more risk averse than men and that gonadal hormones significantly contribute to this sex difference. Gonadal hormones can influence risk-based decision making (i.e., risk taking) by modulating the neurobiological substrates underlying this cognitive process. Indeed, estradiol, progesterone and testosterone modulate activity in the prefrontal cortex, amygdala and nucleus accumbens associated with reward and risk-related information. The use of animal models of decision making has advanced our understanding of the intersection between the behavioral, neural and hormonal mechanisms underlying sex differences in risk taking. This review will outline the current state of this literature, identify the current gaps in knowledge and suggest the neurobiological mechanisms by which hormones regulate risky decision making. Collectively, this knowledge can be used to understand the potential consequences of significant hormonal changes, whether endogenously or exogenously induced, on risk-based decision making as well as the neuroendocrinological basis of neuropsychiatric diseases that are characterized by impaired risk taking, such as substance use disorder and schizophrenia.

Chronic cocaine causes age-dependent increases in risky choice in both males and females.

Individuals who use cocaine exhibit maladaptive decision-making, overweighting rewards, and underweighting potential risks. We previously showed that chronic cocaine self-administration in young adult male rats causes long-lasting increases in risk taking. The present study expanded upon these findings to determine whether effects of cocaine on risk taking depend on the route of cocaine administration and extend to females. To address the former question, rats in Experiment 1 were trained on the Risky Decision-making Task (RDT), received passively administered cocaine, and were retested in the RDT. Surprisingly, passive cocaine had no effect on risk taking. Experiment 2 determined whether cocaine self-administration increases risk taking in females in a manner comparable to males. Males and females were trained in the RDT, underwent cocaine self-administration, and were retested in the RDT. Unexpectedly, cocaine self-administration had no effect on risk taking in either sex. Because Experiments 1 and 2 involved cocaine exposure at a considerably older age than in previous work, Experiments 3 and 4 determined if cocaine effects on risk taking depend on the age of exposure. Rats began cocaine self-administration at postnatal (PN) day 77 (Experiment 3) or passive cocaine injections starting on PN day 63 (Experiment 4) and were tested in the RDT 3 weeks after cocaine cessation. In these experiments, cocaine increased risk taking in both sexes. These results reveal a limited time window during young adulthood of vulnerability to the effects of chronic cocaine on risk taking. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Effects of a high-fat diet on impulsive choice in rats.

INTRODUCTION: Obesity and binge eating disorder are associated with high levels of impulsivity, but the causal role of eating and palatable food in these associations is unclear. Studies in rodents show that a high-fat diet can increase one aspect of impulsivity (impulsive action); it is less clear, however, whether a dissociable aspect of impulsivity (impulsive choice) is similarly affected. Hence, the aim of this study was to ascertain whether chronic exposure to a high-fat diet would alter impulsive choice. METHODS: Male rats were maintained on either a high-fat or control chow diet for two weeks ad libitum. They then underwent equi-caloric food restriction for the duration of the experiment, with each group maintained on their respective diet. To measure impulsive choice, rats were trained on a delay discounting task (DDT) in which they made discrete choices between a lever that delivered a small food reward immediately and a lever that delivered a large food reward accompanied by systematically increasing delays. Upon reaching stable performance on the DDT, rats were given acute systemic injections of amphetamine prior to testing in the DDT to determine whether increased monoamine transmission affected impulsive choice differently in the two diet groups. Lastly, subjects were tested on a progressive ratio schedule of reinforcement to assess motivation for a sucrose reward. RESULTS: There was no significant effect of the high-fat diet on impulsive choice. Further, amphetamine decreased choice of the large, delayed reward (increased impulsive choice) to the same extent in both groups. Exposure to the high-fat diet did, however, increase motivation to obtain a sucrose reward. CONCLUSIONS: These experiments reveal that, under conditions that do not promote weight gain, a chronic high-fat diet does not affect impulsive choice in a delay discounting task. The data are surprising in light of findings showing that this same diet alters impulsive action, and highlight the necessity of further research to elucidate relationships between palatable food consumption and impulsivity.

Regulation of risky decision making by gonadal hormones in males and females.

Psychiatric diseases characterized by dysregulated risky decision making are differentially represented in males and females. The factors that govern such sex differences, however, remain poorly understood. Using a task in which rats make discrete trial choices between a small, "safe" food reward and a large food reward accompanied by varying probabilities of footshock punishment, we recently showed that females are more risk averse than males. The objective of the current experiments was to test the extent to which these sex differences in risky decision making are mediated by gonadal hormones. Male and female rats were trained in the risky decision-making task, followed by ovariectomy (OVX), orchiectomy (ORX), or sham surgery. Rats were then retested in the task, under both baseline conditions and following administration of estradiol and/or testosterone. OVX increased choice of the large, risky reward (increased risky choice), an effect that was attenuated by estradiol administration. In contrast, ORX decreased risky choice, but testosterone administration was without effect in either ORX or sham males. Estradiol, however, decreased risky choice in both groups of males. Importantly, none of the effects of hormonal manipulation on risky choice were due to altered shock sensitivity or food motivation. These data show that gonadal hormones are required for maintaining sex-typical profiles of risk-taking behavior in both males and females, and that estradiol is sufficient to promote risk aversion in both sexes. The findings provide novel information about the mechanisms supporting sex differences in risk taking and may prove useful in understanding sex differences in the prevalence of psychiatric diseases associated with altered risk taking.

Effects of repeated adolescent exposure to cannabis smoke on cognitive outcomes in adulthood.

BACKGROUND: Cannabis (marijuana) is the most widely used illicit drug in the USA, and consumption among adolescents is rising. Some animal studies show that adolescent exposure to delta 9-tetrahydrocannabinol or synthetic cannabinoid receptor 1 agonists causes alterations in affect and cognition that can persist into adulthood. It is less clear, however, whether similar alterations result from exposure to cannabis via smoke inhalation, which remains the most frequent route of administration in humans. AIMS: To begin to address these questions, a rat model was used to determine how cannabis smoke exposure during adolescence affects behavioral and cognitive outcomes in adulthood. METHODS: Adolescent male Long-Evans rats were assigned to clean air, placebo smoke, or cannabis smoke groups. Clean air or smoke exposure sessions were conducted daily during adolescence (from P29-P49 days of age ) for a total of 21 days, and behavioral testing began on P70. RESULTS: Compared to clean air and placebo smoke conditions, cannabis smoke significantly attenuated the normal developmental increase in body weight, but had no effects on several measures of either affect/motivation (open field activity, elevated plus maze, instrumental responding under a progressive ratio schedule of reinforcement) or cognition (set shifting, reversal learning, intertemporal choice). Surprisingly, however, in comparison to clean air controls rats exposed to either cannabis or placebo smoke in adolescence exhibited enhanced performance on a delayed response working memory task. CONCLUSIONS: These findings are consistent with a growing body of evidence for limited long-term adverse cognitive and affective consequences of adolescent exposure to relatively low levels of cannabinoids.

Using rodent models to understand interactions between gambling and substance use.

Substance use is strongly associated with gambling, but the nature of this association can be difficult to determine. Rodents offer the opportunity to test causal models of these relationships through isolation of individual variables of interest. This review describes recent research in rodents showing: a) predisposing factors for both gambling-like behavior and substance use; b) exposure to drugs of abuse increasing gambling-like behavior; c) experience with gambling-like behavior increasing substance use; and d) links between gambling-like behavior and substance use in models of Parkinson's disease therapies. These findings reveal novel relationships between gambling and substance use, and highlight the utility of rodent models for future work in this area.

Testicular hormones mediate robust sex differences in impulsive choice in rats.

Impairments in choosing optimally between immediate and delayed rewards are associated with numerous psychiatric disorders. Such 'intertemporal' choice is influenced by genetic and experiential factors; however, the contributions of biological sex are understudied and data to date are largely inconclusive. Rats were used to determine how sex and gonadal hormones influence choices between small, immediate and large, delayed rewards. Females showed markedly greater preference than males for small, immediate over large, delayed rewards (greater impulsive choice). This difference was neither due to differences in food motivation or reward magnitude perception, nor was it affected by estrous cycle. Ovariectomies did not affect choice in females, whereas orchiectomies increased impulsive choice in males. These data show that male rats exhibit less impulsive choice than females and that this difference is at least partly maintained by testicular hormones. These differences in impulsive choice could be linked to gender differences across multiple neuropsychiatric conditions.

Reward/Punishment-Based Decision Making in Rodents.

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).

Distinct relationships between risky decision making and cocaine self-administration under short- and long-access conditions.

Substance use is strongly associated with impaired decision making, with cocaine use particularly linked to elevated risky and impulsive choice. It is not clear, however, whether such maladaptive decision making is a consequence of cocaine use or instead precedes and predisposes individuals to cocaine use. The current study was designed to specifically address the latter possibility with respect to risky choice in both male and female rats. Rats were first trained in a "Risky Decision-making Task" (RDT), in which they made discrete choices between a small, "safe" food reward and a large, "risky" food reward accompanied by increasing probabilities of mild footshock punishment. After reaching stable performance, rats underwent jugular catheter surgery followed by either short-access cocaine self-administration sessions (2 h, 0.5 mg/kg/infusion) for 5 days or long-access cocaine self-administration sessions (6 h, 0.5 mg/kg/infusion) for 14 days. Under short-access conditions, there was no relationship between risk preference and changes in cocaine intake over time, but greater risk aversion in females predicted greater overall cocaine intake. Under long-access conditions, heightened risk taking predicted greater escalation of cocaine intake over the course of self-administration, supporting the notion that pre-existing risk-taking behavior predicts cocaine intake. Collectively, results from these experiments have implications for understanding and identifying pre-existing vulnerabilities to substance use, which may lead to strategies to prevent development of substance use disorders.

Recent Updates in Modeling Risky Decision Making in Rodents.

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.

Optogenetic dissection of basolateral amygdala contributions to intertemporal choice in young and aged rats.

Across species, aging is associated with an increased ability to choose delayed over immediate gratification. These experiments used young and aged rats to test the role of the basolateral amygdala (BLA) in intertemporal decision making. An optogenetic approach was used to inactivate the BLA in young and aged rats at discrete time points during choices between levers that yielded a small, immediate vs. a large, delayed food reward. BLA inactivation just prior to decisions attenuated impulsive choice in both young and aged rats. In contrast, inactivation during receipt of the small, immediate reward increased impulsive choice in young rats but had no effect in aged rats. BLA inactivation during the delay or intertrial interval had no effect at either age. These data demonstrate that the BLA plays multiple, temporally distinct roles during intertemporal choice, and show that the contribution of BLA to choice behavior changes across the lifespan.

Deconstructing value-based decision making via temporally selective manipulation of neural activity: Insights from rodent models.

The ability to choose among options that differ in their rewards and costs (value-based decision making) has long been a topic of interest for neuroscientists, psychologists, and economists alike. This is likely because this is a cognitive process in which all animals (including humans) engage on a daily basis, be it routine (which road to take to work) or consequential (which graduate school to attend). Studies of value-based decision making (particularly at the preclinical level) often treat it as a uniform process. The results of such studies have been invaluable for our understanding of the brain substrates and neurochemical systems that contribute to decision making involving a range of different rewards and costs. Value-based decision making is not a unitary process, however, but is instead composed of distinct cognitive operations that function in concert to guide choice behavior. Within this conceptual framework, it is therefore important to consider that the known neural substrates supporting decision making may contribute to temporally distinct and dissociable components of the decision process. This review will describe this approach for investigating decision making, drawing from published studies that have used techniques that allow temporal dissection of the decision process, with an emphasis on the literature in animal models. The review will conclude with a discussion of the implications of this work for understanding pathological conditions that are characterized by impaired decision making.