Catharine A. Winstanley

Contrasting Roles of Basolateral Amygdala and Orbitofrontal Cortex in Impulsive Choice

The orbitofrontal cortex (OFC) and basolateral nucleus of the amygdala (BLA) share many reciprocal connections, and a functional interaction between these regions is important in controlling goal-directed behavior. However, their relative roles have proved hard to dissociate. Although injury to these brain regions can cause similar effects, it has been suggested that the resulting impairments arise through damage to different, yet converging, cognitive processes. Patients with OFC or amygdala lesions exhibit maladaptive decision making and aberrant social behavior often described as impulsive. Impulsive choice may be measured in both humans and rodents by evaluating intolerance to delay of reinforcement. Rats with excitotoxic lesions of the BLA and OFC were tested on such a delay-discounting procedure. Although lesions of the BLA increased choice of the small immediate reward, indicating greater impulsivity, OFC lesions had the opposite effect, increasing preference for the larger but delayed reward. The fact that the delay did not devalue the large reward to such an extent in OFC-lesioned animals supports the suggestion that the OFC is involved in updating the incentive value of outcomes in response to devaluation. In contrast, the BLA-lesioned animals markedly decreased their preference for the large reward when it was delayed, potentially because of an inability to maintain a representation of the reward in its absence. This is the first time that lesions to these two structures have produced opposite behavioral effects, indicating their distinct contributions to cognition.

Fractionating impulsivity: contrasting effects of central 5-HT depletion on different measures of impulsive behavior.

Reducing levels of 5-HT in the central nervous system has been associated with increases in impulsive behavior. However, the impulsivity construct describes a wide range of behaviors, including the inability to withhold a response, intolerance to delay of reward and perseveration of a nonrewarded response. Although these behaviors are generally studied using instrumental paradigms, impulsivity may also be reflected in simple Pavlovian tasks such as autoshaping and conditioned activity. This experiment aimed to characterize further the effects of central 5-HT depletion and to investigate whether different behavioral measures of impulsivity are inter-related, thus validating the construct. Rats received intracerebroventricular (ICV) infusions of vehicle (n=10) or the serotonergic neurotoxin 5,7-dihydroxytryptamine (n=12) which depleted forebrain 5-HT levels by about 90%. Lesioned animals showed significant increases in the speed and number of responses made in autoshaping, increased premature responding on a simple visual attentional task, enhanced expression of locomotor activity conditioned to food presentation, yet no change in impulsive choice was observed, as measured by a delay-discounting paradigm. Significant positive correlations were found between responses made in autoshaping and the level of conditioned activity, indicating a possible common basis for these behaviors, yet no correlations were found between other behavioral measures. These data strengthen and extend the hypothesis that 5-HT depletion increases certain types of impulsive responding. However, not all measures of impulsivity appear to be uniformly affected by 5-HT depletion, or correlate with each other, supporting the suggestion that impulsivity is not a unitary construct.

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.

Cortico-limbic-striatal circuits subserving different forms of cost-benefit decision making

Research on the neural basis that underlies decision making in humans has revealed that these processes are mediated by distributed neural networks that incorporate different regions of the frontal lobes, the amygdala, the ventral striatum, and the dopamine system. In the present article, we review recent studies in rodents investigating the contribution of these systems to different forms of cost-benefit decision making and focus on evaluations related to delays, effort, or risks associated with certain rewards. Anatomically distinct regions of the medial and orbital prefrontal cortex make dissociable contributions to different forms of decision making, although lesions of these regions can induce variable effects, depending on the type of tasks used to assess these functions. The basolateral amygdala and the nucleus accumbens play a more fundamental role in these evaluations, helping an organism overcome different costs to obtain better rewards. Dopamine activity biases behavior toward more costly yet larger rewards, although abnormal increases in dopamine transmission can exert opposing actions on different types of decision making. The fact that similar neural circuits are recruited to solve these types of problems in both humans and animals suggests that animal models of decision making will prove useful in elucidating the mechanisms mediating these processes.

Insight into the relationship between impulsivity and substance abuse from studies using animal models.

Drug use disorders are often accompanied by deficits in the capacity to efficiently process reward-related information and to monitor, suppress, or override reward-controlled behavior when goals are in conflict with aversive or immediate outcomes. This emerging deficit in behavioral flexibility and impulse control may be a central component of the progression to addiction, as behavior becomes increasingly driven by drugs and drug-associated cues at the expense of more advantageous activities. Understanding how neural mechanisms implicated in impulse control are affected by addictive drugs may therefore prove a useful strategy in the search for new treatment options. Animal models of impulsivity and addiction could make a significant contribution to this endeavor. Here, some of the more common behavioral paradigms used to measure different aspects of impulsivity across species are outlined, and the importance of the response to reward-paired cues in such paradigms is discussed. Naturally occurring differences in forms of impulsivity have been found to be predictive of future drug self-administration, but drug exposure can also increase impulsive responding. Such data are in keeping with the suggestion that impulsivity may contribute to multiple stages within the spiral of addiction. From a neurobiological perspective, converging evidence from rat, monkey, and human studies suggest that compromised functioning within the orbitofrontal cortex may critically contribute to the cognitive sequelae of drug abuse. Changes in gene transcription and protein expression within this region may provide insight into the mechanism underlying drug-induced cortical hypofunction, reflecting new molecular targets for the treatment of uncontrolled drug-seeking and drug-taking behavior.

The utility of rat models of impulsivity in developing pharmacotherapies for impulse control disorders

High levels of impulsive behaviours are a clinically significant symptom in a range of psychiatric disorders, such as attention deficit hyperactivity disorder, bipolar disorder, personality disorders, pathological gambling and substance abuse. Although often measured using questionnaire assessments, levels of different types of impulsivity can also be determined using behavioural tests. Rodent analogues of these paradigms have been developed, and similar neural circuitry has been implicated in their performance in both humans and rats. In the current review, the methodology underlying the measurement of different aspects of impulsive action and choice are considered from the viewpoint of drug development, with a focus on the continuous performance task (CPT), stop‐signal task (SST), go/no‐go and delay‐discounting paradigms. Current issues impeding translation between animal and human studies are identified, and comparisons drawn between the acute effects of dopaminergic, noradrenergic and serotonergic compounds across species. Although the field could benefit from a more systematic determination of different pharmacological agents across paradigms, there are signs of strong concordance between the animal and human data. However, the type of impulsivity measured appears to play a significant role, with the SST and delay discounting providing more consistent effects for dopaminergic drugs, while the CPT and SST show better predictive validity so far for serotonergic and noradrenergic compounds. Based on the available data, it would appear that these impulsivity models could be used more widely to identify potential pharmacotherapies for impulse control disorders. Novel targets within the glutamatergic and serotonergic system are also suggested.

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.

ΔFosB Induction in Orbitofrontal Cortex Mediates Tolerance to Cocaine-Induced Cognitive Dysfunction

Current cocaine users show little evidence of cognitive impairment and may perform better when using cocaine, yet withdrawal from prolonged cocaine use unmasks dramatic cognitive deficits. It has been suggested that such impairments arise in part through drug-induced dysfunction within the orbitofrontal cortex (OFC), yet the neurobiological mechanisms remain unknown. We observed that chronic cocaine self-administration increased expression of the transcription factor ΔFosB within both medial and orbitofrontal regions of the rat prefrontal cortex. However, the increase in OFC ΔFosB levels was more pronounced after self-administered rather than experimenter-administered cocaine, a pattern that was not observed in other regions. We then used rodent tests of attention and decision making to determine whether ΔFosB within the OFC contributes to drug-induced alterations in cognition. Chronic cocaine treatment produced tolerance to the cognitive impairments caused by acute cocaine. Overexpression of a dominant-negative antagonist of ΔFosB, ΔJunD, in the OFC prevented this behavioral adaptation, whereas locally overexpressing ΔFosB mimicked the effects of chronic cocaine. Gene microarray analyses identified potential molecular mechanisms underlying this behavioral change, including an increase in transcription of metabotropic glutamate receptor subunit 5 and GABAA receptors as well as substance P. Identification of ΔFosB in the OFC as a mediator of tolerance to the effects of cocaine on cognition provides fundamentally new insight into the transcriptional modifications associated with addiction.

The orbitofrontal cortex, impulsivity, and addiction: probing orbitofrontal dysfunction at the neural, neurochemical, and molecular level.

Abstract:  The association between impulsivity and addiction is currently a topic of intense research interest. Investigations into the neurobiological basis of aspects of impulse control have revealed some striking parallels between the brain circuitry and neurochemical systems implicated in drug dependence and impulsive behavior. Both processes are heavily regulated by limbic corticostriatal circuits including the orbitofrontal cortex (OFC) and nucleus accumbens (NAC), and are modulated by dopamine (DA) and serotonin (5‐HT). Hypoactivity within the OFC has been observed in recently abstinent cocaine users, and this is thought to contribute to the cognitive deficits associated with drug abuse, including impairments in impulse control. However, the neurobiological mechanisms underlying these functional and behavioral deficits are unclear. In parallel to observations made in the NAC, recent data indicate that chronic cocaine use also induces the transcription factor ΔFosB in the OFC and that this plays a role in the cognitive sequelae of chronic cocaine administration. In particular, ΔFosB appears to be involved in the development of tolerance to the disruptive effects of acute cocaine on impulsivity and motivation observed after repeated cocaine administration. Increased ΔFosB also contributes to increased impulsivity during withdrawal from the drug. Both effects could be attributed to the up‐regulation of local inhibitory processes in the OFC after over‐expression of ΔFosB and chronic cocaine treatment. Through integrating what is known of the interaction between addictive drugs and impulsivity at the neural, neurochemical, and molecular level, novel insight may be obtained into the multi‐faceted regulation of the addicted state.

Contributions of serotonin in addiction vulnerability

The serotonin (5-hydroxytryptamine; 5-HT) system has long been associated with mood and its dysregulation implicated in the pathophysiology of mood and anxiety disorders. While modulation of 5-HT neurotransmission by drugs of abuse is also recognized, its role in drug addiction and vulnerability to drug relapse is a more recent focus of investigation. First, we review preclinical data supporting the serotonergic raphe nuclei and their forebrain projections as targets of drugs of abuse, with emphasis on the effects of psychostimulants, opioids and ethanol. Next, we examine the role of 5-HT receptors in impulsivity, a core behavior that contributes to the vulnerability to addiction and relapse. Finally, we discuss evidence for serotonergic dysregulation in comorbid mood and addictive disorders and suggest novel serotonergic targets for the treatment of addiction and the prevention of drug relapse.