Fiona D. Zeeb

Serotonergic and Dopaminergic Modulation of Gambling Behavior as Assessed Using a Novel Rat Gambling Task

Pathological gambling (PG) is characterized by persistent, maladaptive gambling behavior, which disrupts personal and professional life. Animal models of gambling behavior could make a significant contribution to improving our understanding of the neural and neurochemical basis of gambling, and the treatment of PG. When gambling, failing to win critically results in the loss of resources wagered as well as the absence of additional gain. Here, we have incorporated these concepts into a novel rat gambling task (rGT), based, in part, on the ‘Iowa’ gambling task (IGT) commonly used clinically to measure gambling-like behavior. Rats choose among four different options to earn as many sugar pellets as possible within 30 min. Each option is associated with the delivery of a different amount of reward, but also with a different probability and duration of punishing time-out periods during which reward cannot be earned. The schedules are designed such that persistent choice of options linked with larger rewards result in fewer pellets earned per unit time. Rats learn to avoid these risky options to maximize their earnings, comparable with the optimal strategy in the IGT. Both d-amphetamine and the 5-HT1A receptor agonist, 8-OH-DPAT, impaired task performance. In contrast, the dopamine D2 receptor antagonist, eticlopride, improved performance, whereas the D1 receptor antagonist, SCH23390, had no effect. These data suggest that both serotonergic and dopaminergic agents can impair and improve gambling performance, and indicate that the rGT will be a useful tool to study the biological basis of gambling.

Contributions of the orbitofrontal cortex to impulsive choice: interactions with basal levels of impulsivity, dopamine signalling, and reward-related cues

RationaleIndividual differences in impulsive decision-making may be critical determinants of vulnerability to impulse control disorders and substance abuse, yet little is known of their biological or behavioural basis. The orbitofrontal cortex (OFC) has been heavily implicated in the regulation of impulsive decision-making. However, lesions of the OFC in rats have both increased and decreased impulsivity in delay-discounting paradigms, where impulsive choice is defined as the selection of small immediate over larger delayed rewards.ObjectivesReviewing the different methods used, we hypothesized that the effects of OFC inactivation on delay discounting may be critically affected by both subjects’ baseline level of impulsive choice and the presence or absence of a cue to bridge the delay between selection and delivery of the large reward.ResultsHere, we show that OFC inactivation increased impulsive choice in less impulsive rats when the delay was cued, but decreased impulsive choice in highly impulsive rats in an uncued condition.ConclusionsProviding explicit environmental cues to signal the delay-to-reinforcement appears to change the way in which the OFC is recruited in the decision-making process in a baseline-dependent fashion. This change may reflect activation of the dopamine system, as intra-OFC infusions of dopamine receptor antagonists increased impulsive choice but only when the delay was cued.

Rodent versions of the iowa gambling task: opportunities and challenges for the understanding of decision-making.

Impaired decision-making is a core problem in several psychiatric disorders including attention-deficit/hyperactivity disorder, schizophrenia, obsessive–compulsive disorder, mania, drug addiction, eating disorders, and substance abuse as well as in chronic pain. To ensure progress in the understanding of the neuropathophysiology of these disorders, animal models with good construct and predictive validity are indispensable. Many human studies aimed at measuring decision-making capacities use the Iowa gambling task (IGT), a task designed to model everyday life choices through a conflict between immediate gratification and long-term outcomes. Recently, new rodent models based on the same principle have been developed to investigate the neurobiological mechanisms underlying IGT-like decision-making on behavioral, neural, and pharmacological levels. The comparative strengths, as well as the similarities and differences between these paradigms are discussed. The contribution of these models to elucidate the neurobehavioral factors that lead to poor decision-making and to the development of better treatments for psychiatric illness is considered, along with important future directions and potential limitations.

Yohimbine Increases Impulsivity Through Activation of cAMP Response Element Binding in the Orbitofrontal Cortex

BACKGROUND Stress can increase impulsivity and has a negative impact on psychiatric outcome. Norepinephrine is heavily implicated in responses to stress, and the alpha(2) antagonist yohimbine is used clinically to study this aspect of the stress response. Yohimbine induces mild anxiety and increases impulsivity in healthy volunteers but has more detrimental effects in some psychiatric populations, triggering mania in bipolar patients and drug craving in substance-dependent individuals. Understanding the mechanism by which yohimbine affects brain function could provide insight into the heightened reaction to stress in these patients. METHODS Yohimbines effects were assessed in rats using the five-choice serial reaction time test of attention and impulse control. We then examined whether yohimbine altered activity of cyclic adenosine monophosphate response element binding (CREB) protein-a transcription factor implicated in the stress response-in brain areas that regulate impulsivity. The behavioral consequences of any changes in CREB activity were subsequently assessed using viral-mediated gene transfer to regionally overexpress CREB or the dominant negative antagonist mCREB. RESULTS Yohimbine increased impulsive responding in rats and selectively increased CREB phosphorylation within the orbitofrontal cortex but not medial prefrontal cortex or nucleus accumbens. Overexpressing mCREB within the orbitofrontal cortex blocked yohimbines effects on impulsivity, whereas overexpressing CREB in this region increased impulsive responding and potentiated the proimpulsive actions of yohimbine. DISCUSSION These data suggest a novel molecular mechanism contributing to impulsivity that may be sensitive to stress. Such findings may improve our understanding of the neurobiological pathways linking the response to stress and impulsivity in both healthy and psychiatric populations.

Functional Disconnection of the Orbitofrontal Cortex and Basolateral Amygdala Impairs Acquisition of a Rat Gambling Task and Disrupts Animals' Ability to Alter Decision-Making Behavior after Reinforcer Devaluation

An inability to adjust choice preferences in response to changes in reward value may underlie key symptoms of many psychiatric disorders, including chemical and behavioral addictions. We developed the rat gambling task (rGT) to investigate the neurobiology underlying complex decision-making processes. As in the Iowa Gambling task, the optimal strategy is to avoid choosing larger, riskier rewards and to instead favor options associated with smaller rewards but less loss and, ultimately, greater long-term gain. Given the demonstrated importance of the orbitofrontal cortex (OFC) and basolateral amygdala (BLA) in acquisition of the rGT and Iowa Gambling task, we used a contralateral disconnection lesion procedure to assess whether functional connectivity between these regions is necessary for optimal decision-making. Disrupting the OFC-BLA pathway retarded acquisition of the rGT. Devaluing the reinforcer by inducing sensory-specific satiety altered decision-making in control groups. In contrast, disconnected rats did not update their choice preference following reward devaluation, either when the devalued reward was still delivered or when animals needed to rely on stored representations of reward value (i.e., during extinction). However, all rats exhibited decreased premature responding and slower response latencies after satiety manipulations. Hence, disconnecting the OFC and BLA did not affect general behavioral changes caused by reduced motivation, but instead prevented alterations in the value of a specific reward from contributing appropriately to cost-benefit decision-making. These results highlight the role of the OFC-BLA pathway in the decision-making process and suggest that communication between these areas is vital for the appropriate assessment of reward value to influence choice.

Dopaminergic modulation of the orbitofrontal cortex affects attention, motivation and impulsive responding in rats performing the five-choice serial reaction time task

Understanding the neurobiological factors underlying individual differences in impulsivity may provide valuable insight into vulnerability to impulse control disorders. Recent data implicate both the orbitofrontal cortex (OFC) and the dopaminergic system in psychiatric disorders associated with high levels of impulsivity, including substance abuse, mania and obsessive-compulsive disorder. However, the consequences of modulating dopaminergic activity within the OFC on impulsive behaviour are largely unknown. The effects of direct intra-OFC infusions of agonists and antagonists at the dopamine D(1) and D(2) receptors were therefore assessed in rats performing the five-choice serial reaction time test (5CSRT) of attention and motor impulsivity. Intra-OFC administration of SCH23390, a D(1) receptor antagonist, decreased impulsive responding in highly impulsive (HI) rats, but did not affect behaviour in less impulsive (LI) animals. Furthermore, the D(2) agonist quinpirole caused significant deficits in task performance, impairing accuracy, increasing omissions and decreasing the number of trials completed, which resembled the effects of systemic administration. In contrast, the D(1) agonist SKF 81297 had little effect on behaviour. Neither agonist increased impulsivity. These data provide partial support for the suggestion that high levels of impulsivity are associated with increased dopamine levels within the OFC, but further indicate that simulating dopamines actions selectively at the D(1) or D(2) receptor cannot reproduce a highly impulsive phenotype. Dopaminergic activity within the OFC may therefore modulate impulsivity indirectly, perhaps in conjunction with other neurotransmitter systems. Furthermore, D(2)-mediated neurotransmission within the OFC could make a more fundamental contribution to cognitive behaviour.

Differential effects of environmental enrichment, social-housing, and isolation-rearing on a rat gambling task: Dissociations between impulsive action and risky decision-making

RationaleDecision-making deficits, measured using the Iowa Gambling Task (IGT), are observed in many psychiatric populations. Additionally, evidence suggests that the environment also influences the development of these same disorders.ObjectiveTo determine the direct influence of the environment on decision-making by utilizing the rat gambling task (rGT), a risky decision-making test modeled after the IGT.MethodsMale rats reared in isolation, in pairs, or in an enriched environment were trained on the rGT as adults. During the rGT, animals chose from four different options. The optimal strategy on the rGT and IGT is the same: to favor options associated with smaller immediate rewards and less punishment/loss. Impulsive action is also measured during rGT performance by recording the number of premature responses made, similar to the five-choice serial reaction time task.ResultsCompared to pair-housed rats, isolated and environmentally enriched rats were slower at learning the optimal strategy. However, following training, only isolation-reared rats chose the disadvantageous options more often. Amphetamine altered decision-making on the rGT in socially housed animals, yet isolates were unaffected. Conversely, amphetamine increased premature responding similarly in all groups. This increase was attenuated by prior administration of a dopamine D1 or D2 antagonist; however, the ability of amphetamine to alter decision-making was not blocked by either drug.ConclusionsHousing environment affects animals’ ability to learn and perform a decision-making task. Additionally, amphetamine’s effect on impulsive action appears to be mediated by the dopaminergic system, whereas its effect on risky decision-making may be mediated by other neurotransmitters.

Dissociable effects of basolateral amygdala lesions on decision making biases in rats when loss or gain is emphasized

Individuals switch from risk seeking to risk aversion when mathematically identical options are described in terms of loss versus gains, as exemplified in the reflection and framing effects. Determining the neurobiology underlying such cognitive biases could inform our understanding of decision making in health and disease. Although reports vary, data using human subjects have implicated the amygdala in such biases. Animal models enable more detailed investigation of neurobiological mechanisms. We therefore tested whether basolateral amygdala (BLA) lesions would affect risk preference for gains or losses in rats. Choices in both paradigms were always between options of equal expected value—a guaranteed outcome, or the 50:50 chance of double or nothing. In the loss-chasing task, most rats exhibited strong risk seeking preferences, gambling at the risk of incurring double the penalty, regardless of the size of the guaranteed loss. In the betting task, the majority of animals were equivocal in their choice, irrespective of bet size; however, a wager-sensitive subgroup progressively shifted away from the uncertain option as the bet size increased, which is reminiscent of risk aversion. BLA lesions increased preference for the smaller guaranteed loss in the loss-chasing task, without affecting choice on the betting task, which is indicative of reduced risk seeking for losses, but intact risk aversion for gains. These data support the hypothesis that the amygdala plays a more prominent role in choice biases related to losses. Given the importance of the amygdala in representing negative affect, the aversive emotional reaction to loss, rather than aberrant estimations of probability or loss magnitude, may underlie risk seeking for losses.

Low Impulsive Action, but not Impulsive Choice, Predicts Greater Conditioned Reinforcer Salience and Augmented Nucleus Accumbens Dopamine Release

Poor impulse control is associated with an increased propensity to develop an addiction and may contribute to relapse as high impulsive subjects appear to attribute greater salience toward drug-paired stimuli. In these studies, we determined whether trait impulsivity also predicts the desire to obtain natural reward-paired stimuli. Rats trained on the 5-choice serial reaction time task to measure impulsive action (Experiment 1) or a delay-discounting task to measure impulsive choice (Experiment 2) were separated into low, intermediate, or high impulsive action (L-IA, I-IA, H-IA) or choice (L-IC, I-IC, H-IC) groups. The motivation to obtain a conditioned stimulus (CS) paired with water-reward was subsequently determined by measuring responding for the CS as a conditioned reinforcer (CRf). Dopamine release in the nucleus accumbens was also measured using in vivo microdialysis. The effects of amphetamine were assessed on all tests. In Experiment 1, amphetamine increased impulsive action in all groups. L-IA rats initially demonstrated the highest responding for the CRf. Amphetamine increased responding for the CRf and this effect was augmented in L-IA rats. Dopamine release following amphetamine was greatest in L-IA subjects. In Experiment 2, amphetamine increased impulsive choice for L-IC and I-IC rats. However, all groups responded similarly for the CRf and dopamine release was moderately greater in L-IC rats. In conclusion, impulsive choice was unrelated to responding for a CRf. L-IA subjects initially attributed enhanced salience to a CS and exhibited greater dopamine release. Lower dopamine release in H-IA rats could result in reduced reinforcing properties of the CRf.

Greater sensitivity to novelty in rats is associated with increased motor impulsivity following repeated exposure to a stimulating environment: implications for the etiology of impulse control deficits

Heightened motor impulsivity and increased novelty‐seeking commonly co‐occur in psychiatric disorders, including drug addiction. However, the relationship between these two phenomena remains unclear. One‐time tests of novelty sensitivity commonly used in preclinical experiments, such as the open‐field or novel‐object test, fail to capture the fact that novelty‐seekers repeatedly experience novel, stimulating situations. The present study therefore investigated whether repeated exposure to a novel, stimulating environment (SE) altered impulsive action. Male Long‐Evans rats were trained to perform the five‐choice serial reaction time task (5CSRTT) which measures motor impulsivity in the form of premature responding as well as attention and motivation. Animals were then exposed to a novel SE (1 h/day for 16 days) immediately prior to the 5CSRTT. Significant increases in premature responding were observed in a subgroup of reactive animals termed high responders (HR‐SE). These rats were not more impulsive at baseline, and levels of impulsivity normalised once exposure to the SE was discontinued. No other aspect of 5CSRTT performance was affected by the SE challenge. We also determined that HR‐SE rats were hyperactive in a novel environment. Biochemical analyses revealed changes in gene and protein expression within the dorsal hippocampus of HR‐SE rats, including decreases in mRNA encoding the dopamine D1 receptor and brain‐derived neurotrophic factor. These results indicate a novel mechanism by which impulsivity and novelty‐reactivity interact that may enhance addiction vulnerability synergistically. Furthermore, studying such context‐induced impulsivity may provide insight into the process by which environmental load precipitates psychiatric symptoms in impulse control disorders.