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Neurobiology of Abnormal Emotion and Motivated Behaviors: Integrating Animal and Human Research
Neurobiology of Abnormal Emotion and Motivated Behaviors: Integrating Animal and Human Research
Neurobiology of Abnormal Emotion and Motivated Behaviors: Integrating Animal and Human Research
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Neurobiology of Abnormal Emotion and Motivated Behaviors: Integrating Animal and Human Research

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Neurobiology of Abnormal Emotion and Motivated Behaviors: Integrating Animal and Human Research pulls together world-renowned leaders from both animal and human research, providing a conceptual framework on how neuroscience can inform our understanding of emotion and motivation, while also outlining methodological commonalities between animal and human neuroscience research, with an emphasis on experimental design, physiological recording techniques and outcome measures. Typically, researchers investigating the neurobiology of emotions focus on either animal models or humans. This book brings the two disciplines together to share information and collaborate on future experimental techniques, physiological measures and clinical outcomes.

  • Integrates animal and human research to aid readers in discovering a clear path forward for translating basic science to clinical applications
  • Provides overviews of the most recent research into the neuroscience behind maladaptive behaviors and psychiatric disorders
  • Explores the commonalities in methods and outcome measures between animal and human researchers and how those commonalities can be harnessed for future collaboration and translational work
LanguageEnglish
Release dateMay 3, 2018
ISBN9780128136942
Neurobiology of Abnormal Emotion and Motivated Behaviors: Integrating Animal and Human Research

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    Neurobiology of Abnormal Emotion and Motivated Behaviors - Susan Sangha

    forward.

    Section I

    Emotion-Related Impulsivity Across Disorders and Species

    Outline

    1 Using Preclinical Models to Understand the Neural Basis of Negative Urgency

    2 Emotion-Related Impulsivity and the Mood Disorders

    1

    Using Preclinical Models to Understand the Neural Basis of Negative Urgency

    Michael T. Bardo¹, Virginia G. Weiss¹ and George V. Rebec²,    ¹University of Kentucky, Lexington, KY, United States,    ²Indiana University Bloomington, Bloomington, IN, United States

    Abstract

    Negative urgency is a facet of impulsivity that is known to be associated with problematic substance use, as well as a host of other health-related negative outcomes. The urgency, premediation (lack of), perseverance (lack of), sensation seeking (UPPS) scale is used to measure negative urgency in humans. Recent evidence indicates that high and low negative urgency subjects respond differently on a reward omission task using monetary incentives. Following omission of an expected reward, high-urgency subjects are more frustrated and display greater impulsive responding compared to low-urgency subjects. This task has also been used in rats to investigate the neurobiology of negative urgency. Converging evidence now indicates that a neural system involving interconnections between the prefrontal cortex and amygdala may play a key role in individual differences in negative urgency. This work may inform prevention scientists and practitioners implementing drug abuse prevention and treatment interventions.

    Keywords

    Negative urgency; drug abuse; reward omission; prefrontal cortex; amygdala

    In this Chapter

    Introduction 3

    Current Models of Negative Urgency 4

    Human Models 4

    Animal Models 5

    Neurobiological Mechanisms of Negative Urgency 11

    Future Directions 15

    Highlights 16

    Acknowledgment 16

    References 16

    Further Reading 20

    Acknowledgment

    This research was supported by NIH grants P50 DA05312 and T32 DA016176.

    Introduction

    Translational research that is bidirectional between preclinical and clinical models can be a daunting task, as there are many domains of human life such as language and personality that are not translated readily between human and nonhuman animals. With few exceptions (Gosling, 2001), preclinical researchers are reluctant to use terms that imply that laboratory animals have personality traits akin to those found in humans. Instead, preclinical researchers most often refer to individual differences or endophenotypes, rather than personality traits. However, a strong case has been made that ecologically relevant individual differences in various species include such traits as aggressiveness, fearfulness, sociability, and activity (McNamara, Stephens, Dall, & Houston, 2009), and that these traits are heritable.

    This chapter will outline some methods that our laboratory and others have been pursuing to develop a preclinical model of negative urgency. Toward this goal, we first define negative urgency as a measureable trait in humans and provide evidence to show its importance in understanding impulsivity-related negative health consequences. Second, toward the development of a preclinical model for negative urgency, we show how a reward omission task in both humans and rats produces impulsive rash actions, suggesting that a reward omission task may be a useful model of negative urgency and that individual differences in this task may be predictive of negative health outcomes such as drug abuse. Third, we describe some preliminary results that characterize some of the neurobiological mechanisms that may underlie individual differences in negative urgency. Finally, directions for future research are offered.

    Current Models of Negative Urgency

    Human Models

    Impulsivity has been the subject of intense investigation due to its association with many health-related negative outcomes, including drug abuse (Weafer, Mitchell, & de Wit, 2014). Both clinical and preclinical models have been developed to measure impulsivity. In humans, impulsivity is known to be a multifaceted construct that can be defined in many ways. According to Depue and Collins (1999), self-report measures of impulsivity comprise a heterogeneous cluster of lower-order traits that include terms such as impulsivity, sensation seeking, risk taking, novelty seeking, boredom susceptibility, and unorderliness. Dick et al. (2010) have commented on the abundance of different measures (both self-report and laboratory based) used to quantify impulsivity and have concluded that these measures are not highly correlated and do not load onto a single factor.

    At the behavioral level, definitions of impulsivity also have been categorized into various types, such as impulsive choice, impulsive action, and/or inattention (Winstanley, Olausson, Taylor, & Jentsch, 2010). While there is no consensus in the field about how to categorize these various behavioral types of impulsivity, they are useful for integrating preclinical and clinical work across human and nonhuman animals. To date, however, these types of impulsivity have been defined primarily by task performance that emphasizes the role of behavioral flexibility and cognitive decision-making (cold cognition). In this chapter, we will provide evidence that, similar to clinical models, preclinical models can be used to investigate emotion-based rash action (hot cognition). In particular, we will focus on recent work that has sought to develop an animal model of negative urgency.

    Impulsivity in humans can be parsed into at least four main facets based on the UPPS scale (Whiteside & Lynam, 2001). These facets are: (1) Urgency, the tendency to experience strong impulses while under a negative mood; (2) (Lack of) Premeditation, the tendency to think about consequences of an act beforehand; (3) (Lack of) Perseverance, the ability to remain focused on projects and resist distraction; and (4) Sensation Seeking, the tendency to enjoy exciting and risky activities. In subsequent work, urgency was parsed into two separate factors, negative urgency and positive urgency (Cyders & Smith, 2008), thus prompting the UPPS to be revised to UPPS-P. While both negative and positive urgency relate to a disposition to engage in rash action, the rash action stems from events engendering either negative or positive affect, respectively. Although negative and positive urgency may be related differently to risky behavior, the current chapter concentrates primarily on negative urgency.

    Negative urgency has been established using convergent and discriminant validity assessment (Miller, Vachon, & Lynam, 2009) and is viewed to be a trait-based tendency to act rashly under times of negative affect, rather than a state-based response to affect. Although state-based affect is known to increase impulsive behavior (Tice, Bratslavsky, & Baumeister, 2001), it does so regardless of individual differences in facets of impulsivity. Thus, as envisioned here, negative urgency is a stable individual difference that confers risk for maladaptive behavior and may be a useful targeting variable for preventive interventions.

    While all facets of the UPPS have been linked to risky behavior, negative urgency relates most consistently to problem drug and alcohol use (Fischer & Smith, 2008; Menary et al., 2015). This contrasts with sensation seeking, which may be more closely associated with early initiation (experimentation) of drug use (Horvath, Milich, Lynam, Leukefeld, & Clayton, 2004; Wills, Vaccaro, & McNamara, 1994); this also contrasts with disinhibition, which is most closely associated with escalation of use after initiation, as occurs with stimulant self-administration (Gipson & Bardo, 2009) or binge drinking (Fillmore & Weafer, 2011). Given the link between negative urgency and risk for drug abuse, it would be beneficial to develop a preclinical model of negative urgency so the neurobiological connections that link negative urgency and drug use could be studied under highly controlled laboratory conditions.

    Animal Models

    As expected based on evolutionary theory, individual differences within any species may have a selective advantage to be retained within the gene pool. While selected phenotypic traits are often anatomically or physiologically based, there is also selective pressure based on individual differences in the expression of behavioral traits. Moreover, within a controlled setting, selective breeding of behavioral traits can be used to produce genetic lines showing distinct variations in the selected trait. From a psychological perspective, it is valuable when a personality trait in humans is back-translated to animals so that selective breeding procedures can be applied to study the trait of interest. For example, selective breeding has been used to derive rodent lines based on a wide variety of neurobehavioral phenotypes, including saccharin preference (Carroll, Morgan, Anker, Perry, & Dess, 2008), anxiety (Bailey & Crawley, 2009), aggression (Sandnabba, 1996), and drug abuse vulnerability (Phillips & Shabani, 2015).

    While sensation seeking and novelty seeking have been modeled in laboratory animals (Belin, Mar, Dalley, Robbins, & Everitt, 2008), there is no widely accepted animal model for negative urgency. To address this gap, our laboratory has developed a reward omission task based on the classic work on frustrative nonreward by Amsel (1962), and more recent work by Burokas, Gutierrez-Cuesta, Martin-Garcia, and Maldonado (2012) and Dudley and Papini (1997). Although omission of an expected reward is an aversive event that suppresses ongoing operant responding (Purgert, Wheeler, McDannald, & Holland, 2012), Amsel demonstrated that an after-effect of an aversive event was an invigoration of appetitive behavior. Invigorated behavior was revealed experimentally using a runway alley with two goal boxes, one in the middle and one at the end of the alley (Amsel & Roussel, 1952). Rats learned to earn food from the middle box and then traverse the alley to the end goal box for another food reward. On occasion, however, food was omitted from the first goal box, and running speed to the end goal box was measured. Results demonstrated that running speed to the end box was faster following nonreward than following reward in the middle goal box. While the interpretation of this reinforcement-omission effect (ROE) has been somewhat controversial using species other than mammals (Stout, Muzio, Boughner, & Papini, 2002), in rats it has been interpreted to reflect frustration or negative affective value.

    Amsel’s runway alley task has been adapted to also include different operant-based procedures. In one version (Wookey & Strongman, 1974), rats were trained to respond on two fixed ratio (FR) 25 components separated by a 10-s signaled interval in which food was delivered at the end of each component. Following acquisition, rats were then reinforced on only 50% of the initial FR25 components, and response performance in the second FR25 component was compared following either reinforced or nonreinforced trials. Similar to the runway alley task, a facilitation of responding was obtained following omission of expected reward. Interestingly, this study also included a separate group of rats trained without any reward in the first FR25 component and then was tested with reward on 50% of the initial FR25 components. In contrast to omission of expected reward, there was no significant change in response performance in the second FR25 component following presentation of an unexpected reward. Thus the conclusion of this study was that rats exhibit a frustration effect (negative urgency), but not an elation effect (positive urgency).

    We have adapted these basic findings to serve toward developing a behavioral model for negative urgency in humans and rats (Gipson et al., 2012). In human subjects, the laboratory task involved two components: (1) a Pavlovian component in which a visual cue signaled that a monetary reward was delivered; and (2) an operant component in which subjects were required to respond on a clicker button 100 times (FR100) in order to earn money. After training on both components separately, the two components were alternated within a daily session. On rare occasion, the Pavlovian cue was not followed by the expected reward and the change in operant response rate on the FR100 was measured. Using this task, we found that low-urgency subjects (based on the UPPS) did not differ in operant responding on either reward or omission trials, whereas high-urgency subjects showed enhanced responding on omission trials compared to reward trials. This invigorated operant responding was associated with self-reported frustration, as high-urgency subjects were more frustrated than low-urgency subjects following reward omission. These results are important because they demonstrate that negative effect (frustration) engenders impulsive action that motivates appetitive impulsive responding.

    Next, we back-translated the negative urgency task developed in humans to rats. Instead of using monetary rewards, rats were given food reward. Using a standard 2-lever operant conditioning chamber, rats were trained to receive food pellets in two different alternating components. The first component was a simple Pavlovian conditioning procedure in which a 5-s light cue signaled the automatic delivery of a food pellet; no response was required. The second component was a 2-m operant conditioning procedure that required 10 responses on one of the two levers (FR10) for a delivery of a food pellet. Each daily session consisted of 32 trials in which the Pavlovian component was followed by the operant component, with each trial separated by a 10-s intertrial interval. After stable performance in the operant conditioning component was achieved, rats were then tested for their reactivity to reward omission. The test consisted of 24 reward trials and 8 omission trials, randomly intermixed. Reward trials were identical to those presented in the baseline phase; omission trials were similar to reward trials, except no pellet was delivered in the initial Pavlovian component. Negative urgency was defined as an increase in responding following omission trials compared to responding following reward trials.

    Like humans, rats showed enhanced responding (negative urgency) for food following omission trials compared to reward trials. The reward omission effect in rats was observed regardless of whether food restriction or free feed was implemented in the home cage. Since food restricted rats showed overall higher rates of operant responding compared to free feed rats, these results show that the reward omission effect occurs independent of baseline rates of ongoing behavior.

    In a separate experiment, Gipson et al. (2012) used the general procedures described previously, except that a unit dose of i.v. amphetamine (0.03 or 0.1 mg/kg/infusion), rather than a food pellet, was used as the reinforcer in the operant conditioning phase of the negative urgency task. Similar to the results with food reinforcement, reward omission increased responding for both doses of amphetamine and this reward omission effect was observed across at least three repeated test sessions. Thus frustrative nonreward appears to nonspecifically invigorate various operant-based behaviors, including drug and nondrug reinforcement contingencies.

    One potential problem with this reward omission task is that impulsive behavior engendered may not be characterized as maladaptive because the increase in operant responding following nonreward yields more food. This contrasts with the view that negative urgency is maladaptive (Derefinko, DeWall, Metze, Walsh, & Lynam, 2011). To address this issue, we developed a modified version of the task. Similar to the original version, the modified task is divided into a Pavlovian component and an operant component. However, in the modified version, the schedule of reinforcement during the operant component was changed from an FR10 to a differential reinforcement for low rate of responding (DRL) schedule. For the DRL schedule, animals were required to wait 5 s before responding on the lever one time to receive a food reinforcer (i.e., DRL 5 s); a premature response that occurred prior to the 5-s duration was not reinforced, and it restarted the timer. The reason for the change in reinforcement schedule is that impulsive responding on the modified task no longer yields a gain in food pellets, but instead yields a loss in food pellets, thus indicating a maladaptive outcome.

    Using this modified reward omission task, our laboratory investigated whether individual differences in negative urgency predicted subsequent acquisition of amphetamine self-administration. Rats were first trained on the reward omission task using food reinforcement and then were divided into high- and low-urgency groups, using a median split based on a response efficiency ratio. The response efficiency ratio for individual rats was defined by the percentage of responses that were reinforced on the DRL 5-s schedule; note that high efficiency ratios represent low impulsivity (low urgency), whereas low efficiency ratios represent high impulsivity (high urgency).

    As shown in Fig. 1.1, based on the performance of all rats tested, efficiency ratios increased with training on the DRL 5-s schedule and stabilized such that approximately 70% of all responses were reinforced (Fig. 1.1A). When rats were tested on a reward omission session (24 reward trials and 8 omission trials, randomly intermixed), the efficiency ratio was significantly lower following reward omission trials compared to reward trials (Fig. 1.1B), indicative of negative urgency.

    Figure 1.1 (A) Mean (±SEM) efficiency ratio from all rats performing on DRL 5-s task across training sessions (n=18). (B) Mean (±SEM) efficiency ratio from all rats performing on DRL 5-s task following either reward or omission trials on the test day; asterisk (*) represents significant difference from reward trials, P<0.05. (C) Mean (±SEM) efficiency ratio from rats split into high- and low-urgency groups based on a median split of performance on DRL 5-s task following either reward or omission trials on the test day; asterisk (*) represents significant difference from reward trials, P<0.05. (D) Mean (±SEM) number of amphetamine infusions for high- and low-urgency groups using an incrementing fixed ratio (FR) schedule across sessions. (E) Mean (±SEM) number of responses on the previously amphetamine-reinforced active lever in high- and low-urgency groups across extinction sessions.

    Following assessment of performance on the reward omission task using food reinforcement, a median split was used to categorize rats into two subgroups (high vs low urgency) based on a median split of the response efficiency ratio scores (Fig. 1.1C). Each of these groups then underwent acquisition and extinction of amphetamine self-administration using a unit dose of 0.03 mg/kg. Amphetamine self-administration was assessed across incrementing FR schedules, starting with an FR1 and terminating with an FR5. Following this acquisition phase, sessions were continued, but amphetamine infusions were terminated to observe the rate of extinction.

    During the acquisition phase, there were no significant differences between groups in amphetamine self-administration (Fig. 1.1D), suggesting the reinforcing effect of amphetamine did not differ between groups. During the extinction phase, ANOVA revealed a main effect of session, with responding decreasing across sessions in both high- and low-urgency groups (P<0.001), thus demonstrating extinction. More importantly, there was also a main effect of group, with high-urgency rats responding more than low-urgency rats collapsed across sessions (P<0.05); there was no significant interaction (P>0.05; Fig. 1.1E). These latter results indicate that high-urgency rats displayed a greater persistence of responding than low-urgency rats when amphetamine was no longer available. This suggests that negative urgency is a useful predictor of preservative responding associated with the incentive value of drug-associated cues, consistent with evidence in humans (Chester, Lynam, Milich, & DeWall, 2016).

    It is somewhat puzzling why individual differences in the reward omission task predicted differences in preservative responding during the extinction phase, but not rates of intake during the acquisition phase. However, using the short access (1 hour) session, the amphetamine infusion rate was relatively low, likely due to the relatively prolonged half-life of amphetamine (Honecker & Coper, 1975). It may be important in future work to examine differences between high and low negative urgency groups using an extended access paradigm, which yields escalated use that is more indicative of dysregulated or problematic use (Ahmed & Koob, 1998), as negative urgency in humans is related to problematic drug use more than regular use (Fischer & Smith, 2008).

    Considering that human cocaine abusers show increased negative urgency (Albein-Urios et al., 2013), we also recently assessed how prior experience with cocaine influences the expression of this trait in rats (Barker & Rebec, 2016). In this preclinical study, 2 weeks after a binge schedule of cocaine administration, rats were trained on the same food reward omission task described earlier using an FR10. Negative urgency was evident in two different behavioral responses depending on the cocaine dose. In rats that had been maintained on a low dose cocaine binge (10–20 mg/kg), the latency to press a lever for food decreased significantly on omission trials compared to vehicle controls. The actual number of lever presses on omission trials also significantly increased above control in rats previously exposed to the high-dose cocaine binge (20–40 mg/kg). Thus binge cocaine enhanced the behavioral markers of negative urgency in a dose-dependent fashion. Interestingly, these effects of cocaine on latency and lever pressing only emerged across multiple days of reward omission testing, indicating that cocaine interfered with the rate of adaptation to reward omission.

    Because cocaine inhibits the dopamine transporter (DAT) and blocks dopamine reuptake (Di Chiara & Imperato, 1988), Barker and Rebec (2016) also examined a separate group of rats that received repeated injections of RTI-113, a selective dopamine transport inhibitor. When tested for negative urgency 2 weeks later, these animals failed to resemble either cocaine dose group, but simply showed a decrease in lever pressing across all days of reward omission testing. Thus the effects of cocaine on negative urgency cannot be explained by dopamine uptake inhibition alone, although pharmacodynamic differences between cocaine and RTI-113 in the temporal properties of dopamine transport binding could complicate this interpretation (Kimmel et al., 2008). Nevertheless, the broad action of cocaine on all monoamine transporters (norepinephrine and serotonin, as well as dopamine), which in turn can trigger adaptations in multiple downstream circuits (Wolf, 2010), is likely to account for the complex psychomotor alterations that emerge following withdrawal from binge

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