Nucleus accumbens and impulsivity

The multifaceted concept of impulsivity implies that different impulsivity aspects, mediated by different neural processes, influence behavior at different levels. The nucleus accumbens (NAc) is a key component of the neural processes regulating impulsivity. In this review, we discuss the findings of lesion studies in animals and functional imaging studies in humans focusing on the role of the NAc in impulsivity. Evidence supports that the extent and pattern of involvement of the NAc, and its subregions, the core and the shell, vary among different facets of impulsivity. Data from imaging studies reviewed in this article suggest the involvement of the ventral striatum/NAc in impulsive choice. Findings of animal studies indicate that lesions of the NAc core subregion facilitated impulsivity in tasks involving intertemporal choice, and promoted a risk-averse, less impulsive, tendency in tasks involving options with probability differences. Modification of neurotransmitter activity, especially of dopamine, which is proposed to underlie the changes observed in functional imaging studies, has been shown to influence afferent input pattern in the NAc and the generation of the behavioral output. Parameters of behavioral tasks reflecting response inhibition function are altered by neurochemical interventions and local electrical stimulation in both the core and the shell subregions. In toto, NAc's pattern of neuronal activity, either genetically determined or acquired, has a critical impact on the interindividual variation in the expression of impulsivity. Nevertheless, the NAc is not the only substrate responsible for impulsivity and it is not involved in each facet of impulsivity to the same extent.     

Role of glutamate receptors in nucleus accumbens core and shell in spatial behaviour of rats

The nucleus accumbens (NAC) is considered to be an important neural interface between corticolimbic and motor systems of the brain. Several studies have shown that the NAC is not only involved in motivation and reward-related processes but also in spatial behavior. We here investigated the involvement of different glutamate receptor subclasses within NAC core and shell subregions on behavior in a radial-maze. Rats were first trained in a four-arm-baited eight-arm radial maze task for baseline performance. Thereafter, the effects of microinjection of the nonselective glutamate receptor antagonist kynurenic acid (4.5 microg), the NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (1 microg) and the non-NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (0.75 microg) in NAC core and shell were tested on reference memory errors (RME) and working memory errors (WME). Moreover, the choice pattern of entries and duration of arm-entries were evaluated. Microinjection of all drugs increased RME. Additionally, non-NMDA receptor blockade in NAC shell but not core increased WME. After microinjection of all drugs into NAC core and shell rats preferentially choose the arms next to the previously visited arm. This work shows that glutamate receptors in both NAC subregions are important for spatial behavior. The deficits seen after glutamate receptor blockade may not be working- or reference memory-related but caused by a switch from a memory-dependent allocentric strategy to an egocentric response strategy.     

The basolateral amygdala differentially regulates conditioned neural responses within the nucleus accumbens core and shell

The ability to process information regarding reward-predictive cues involves a diverse network of neural substrates. Given the importance of the nucleus accumbens (NAc) and the basolateral amygdala (BLA) in associative reward processes, recent research has examined the functional importance of BLA–NAc interactions. Here, multi-neuron extracellular recordings of NAc neurons coupled to microinfusion of GABAA and GABAB agonists into the BLA were employed to determine the functional contribution of the BLA to phasic neural activity across the NAc core and shell during a cued-instrumental task. NAc neural response profiles prior to BLA inactivation exhibited largely indistinguishable activity across the core and shell. However, for NAc neurons that displayed cue-related increases in firing rates during the task, BLA inactivation significantly reduced this activity selectively in the core (not shell). Additionally, phasic increases in firing rate in the core (not shell) immediately following the lever press response were also significantly reduced following BLA manipulation. Concurrent with these neural changes, BLA inactivation caused a significant increase in latency to respond for rewards and a decrease in the percentage of trials in which animals made a conditioned approach to the cue. Together, these results suggest that an excitatory projection from the BLA provides a selective contribution to conditioned neural excitations of NAc core neurons during a cued-instrumental task, providing insight into the underlying neural circuitry that mediates responding to reward-predictive cues.     

Dissociable roles of dopamine within the core and medial shell of the nucleus accumbens in memory for objects and place

There is increasing focus on the role of the nucleus accumbens (NAc) in learning and memory, but there is little consensus as to how the core and medial shell subregions of the NAc contribute to these processes. In the current experiments, we used spontaneous object recognition to test rats with 6-hydroxydopamine lesions targeted at the core or medial shell of the NAc on a familiarity discrimination task and a location discrimination task. In the object recognition variant, control animals were able to discriminate the novel object at both 24-hr and 5-min delay. However, in the lesion groups, performance was systematically related to dopamine (DA) levels in the core but not the shell. In the location recognition task, sham-operated animals readily detected the object displacement at test. In the lesion groups, performance impairment was systematically related to DA levels in the shell but not the core. These results suggest that dopamine function within distinct subregions of the NAc plays dissociable roles in the modulation of memory for objects and place.     

Stimulus-specific and differential distribution of activated extracellular signal-regulated kinase in the nucleus accumbens core and shell during Pavlovian-instrumental transfer

The ability of reward-predictive cues to potentiate reward-seeking behavior—a phenomenon termed Pavlovian-instrumental transfer (PIT)—depends on the activation of extracellular signal-regulated kinase (ERK) in the nucleus accumbens (NAc). Here, we utilized immunohistochemistry to investigate the subregional pattern of ERK activation during PIT, and the contribution of different elements in the PIT condition to the distribution of ERK signaling in the NAc of rats. We found that the occurrence of reward-seeking behavior (lever pressing) did not affect ERK activation in either the core or the shell of the NAc. In contrast, presentation of the reward-predictive cue (auditory conditioned stimulus) caused a significant increase in ERK activation in both subregions of the NAc, with the effect being slightly more robust in the core than the shell. Different from the pattern evoked by the reward-predictive cue, presentation of the reward itself (food pellets) had no effect on ERK activation in the core but caused a pronounced increase in ERK activation in the shell. Taken together, our results demonstrate that ERK signaling in the NAc during PIT involves both the core and the shell and is driven by the conditioned cue irrespective of whether the situation permits engagement in reward-seeking behavior. Furthermore, our results show that the subregional distribution of ERK signaling in the NAc evoked by rewards differs from that evoked by cues that predict them. The stimulus-specific differential pattern of ERK signaling described here may present the molecular complement to stimulus-specific increases in NAc cell firing reported previously.     

Differential control over cocaine-seeking behavior by nucleus accumbens core and shell

Nucleus accumbens (NAc) dopamine is widely implicated in mediating the reinforcing effects of drugs of abuse. However, the precise function of the NAc itself in drug self-administration has been difficult to establish. Here we show a neural double-dissociation of the behavioral processes that underlie cocaine self-administration in rats. Whereas selective excitotoxic lesions of the NAc core had only a minor effect on the acquisition of responding for cocaine under a standard schedule of continuous reinforcement, these lesions profoundly impaired the acquisition of drug-seeking behavior that was maintained by drug-associated conditioned reinforcers and assessed using a second-order schedule of cocaine reinforcement. In contrast, selective excitotoxic lesions of the NAc shell did not impair drug self-administration or the acquisition of cocaine-seeking, but they did attenuate the psychostimulant effects of cocaine. These results further our understanding of how the NAc controls drug-seeking and drug-taking behavior.     

Age of onset of marijuana use impacts inhibitory processing

Difficulties in the ability to successfully inhibit impulsive behaviors have been reported in marijuana (MJ) smokers, yet few studies have made direct comparisons between early (prior to age 16) and late (age 16 or later) onset MJ smokers, specifically during behavioral inhibition tasks. The current study utilized the Multi-Source Interference Task (MSIT) during functional magnetic resonance imaging (fMRI) in chronic, heavy MJ smokers and healthy non-MJ smoking controls which revealed a more focal pattern of anterior cingulate activity in controls relative to smokers. Early onset smokers had more focal activation but tended to make more errors of commission relative to late onset smokers, suggesting a possible neural adaptation despite difficulty with behavioral inhibition. Further investigation is warranted, as early exposure to MJ may result in reorganization of critical brain regions.     

Behavioral models of impulsivity in relation to ADHD: translation between clinical and preclinical studies

Impulsivity, broadly defined as action without foresight, is a component of numerous psychiatric illnesses including attention deficit/hyperactivity disorder (ADHD), mania and substance abuse. In order to investigate the mechanisms underpinning impulsive behavior, the nature of impulsivity itself needs to be defined in operational terms that can be used as the basis for empirical investigation. Due to the range of behaviors that the term impulsivity describes, it has been suggested that impulsivity is not a unitary construct, but encompasses a variety of related phenomena that may differ in their biological basis. Through fractionating impulsivity into these component parts, it has proved possible to devise different behavioral paradigms to measure various aspects of impulsivity in both humans and laboratory animals. This review describes and evaluates some of the current behavioral models of impulsivity developed for use with rodents based on human neuropsychological tests, focusing on the five-choice serial reaction time task, the stop-signal reaction time task and delay-discounting paradigms. Furthermore, the contributions made by preclinical studies using such methodology to improve our understanding of the neural and neurochemical basis of impulsivity and ADHD are discussed, with particular reference to the involvement of both the serotonergic and dopaminergic systems, and frontostriatal circuitry.     

Opposing roles for the nucleus accumbens core and shell in cue-induced reinstatement of food-seeking behavior

Reinstatement of previously extinguished instrumental responding for drug-related cues has been used as an animal model for relapse of drug abuse, and is differentially affected by inactivation of the core and shell subregions of the nucleus accumbens (NAc). To compare the roles of these subregions in reinstatement induced by cues associated with natural and drug rewards, the present study assessed the effects of inactivation of the NAc core and shell on cue-induced reinstatement of food-seeking behavior. Rats acquired a lever pressing response for food reward paired with a light/tone conditioned stimulus (CS). They were then subjected to extinction, where both food and the CS were withheld. Reinstatement of responding was measured during response-contingent presentations of the CS. Following saline infusions into the NAc core or shell, rats displayed a significant increase in lever pressing during reinstatement sessions. Inactivation of the core, induced by infusion of GABA agonists muscimol and baclofen, attenuated responding for the CS, but did not affect pavlovian approach toward the food receptacle. In contrast, inactivation of the shell had the opposite effect, potentiating responding relative to vehicle treatments. These data suggest that the NAc core and shell play opposing, yet complementary roles in mediating the influence that food-associated conditioned stimuli exert over behavior. The core enables reward-related stimuli to bias the direction and vigor of instrumental responding. In contrast, the shell facilitates alterations in behavior in response to changes in the incentive value of conditioned stimuli. The fact that the NAc core appears to play a similar role in cue-induced reinstatement induced by both natural and drug rewards suggests that this region of the ventral striatum may be a final common pathway through which both drug- and food-associated stimuli may influence the direction and magnitude of ongoing behavior.     

Dopamine receptor expression and distribution dynamically change in the rat nucleus accumbens after withdrawal from cocaine self-administration

Dopamine receptors (DARs) in the nucleus accumbens (NAc) are critical for cocaine's actions but the nature of adaptations in DAR function after repeated cocaine exposure remains controversial. This may be due in part to the fact that different methods used in previous studies measured different DAR pools. In the present study, we used a protein crosslinking assay to make the first measurements of DAR surface expression in the NAc of cocaine-experienced rats. Intracellular and total receptor levels were also quantified. Rats self-administered saline or cocaine for 10 days. The entire NAc, or core and shell subregions, were collected one or 45 days later, when rats are known to exhibit low and high levels of cue-induced drug seeking, respectively. We found increased cell surface D1 DARs in the NAc shell on the first day after discontinuing cocaine self-administration (designated withdrawal day 1, or WD1) but this normalized by WD45. Decreased intracellular and surface D2 DAR levels were observed in the cocaine group. In shell, both measures decreased on WD1 and WD45. In core, decreased D2 DAR surface expression was only observed on WD45. Similarly, WD45 but not WD1 was associated with increased D3 DAR surface expression in the core. Taking into account many other studies, we suggest that decreased D2 DAR and increased D3 DAR surface expression on WD45 may contribute to enhanced cocaine-seeking after prolonged withdrawal, although this is likely to be a modulatory effect, in light of the mediating effect previously demonstrated for AMPA-type glutamate receptors.     

Individual differences in offensive aggression in golden hamsters: A model of reactive and impulsive aggression?

In humans, reactive aggression is associated with impulsivity. The purpose of this study is to relate reactive and impulsive aggression in humans with offensive aggression in animals and identify neurobiological correlates associated with certain forms of the behavior. We predicted that individual differences in offensive aggression are associated with individual differences in impulsivity. Adult male hamsters were repeatedly tested for offensive responses and divided into High-Aggression or Low-Aggression groups. They were then trained and tested under a delay-discounting paradigm to assess impulsivity. High-Aggression animals consistently attacked and bit more frequently and faster, and showed highly repetitive behavior, indicated by repeated attacks per contact bout. In addition, these animals engaged in more fragmented and shorter contact bouts. During impulsivity testing, High-Aggression animals preferred immediate smaller rewards over delayed larger rewards. Furthermore, 5-HT and vasopressin (AVP) innervation was compared between the groups. High-Aggression animals showed decreased 5-HT varicosities in several key brain areas involved in aggressive and/or impulsive behavior and decreased AVP fibers in the anterior hypothalamus. Together, these data show a convergence of behavioral phenotypes through individual differences in offensive aggression and impulsivity. As such, this association provides support for an animal model of reactive and impulsive aggression. Furthermore, this behavioral convergence is supported by a concurrent reduction in 5-HT innervation of brain areas controlling aggression and impulsivity, providing a common neural mechanism for this phenotype.     

Involvement of dopaminergic mechanisms in the nucleus accumbens core and shell subregions in the expression of fear conditioning

The involvement of dopamine (DA) mechanisms in the nucleus accumbens (NAC) in fear conditioning has been proposed by many studies that have challenged the view that the NAC is solely involved in the modulation of appetitive processes. However, the role of the core and shell subregions of the NAC in aversive conditioning remains unclear. The present study examined DA release in these NAC subregions using microdialysis during the expression of fear memory. Guide cannulae were implanted in rats in the NAC core and shell. Five days later, the animals received 10 footshocks (0.6 mA, 1 s duration) in a distinctive cage A (same context). On the next day, dialysis probes were inserted through the guide cannulae into the NAC core and shell subregions, and the animals were behaviorally tested for fear behavior either in the same context (cage A) or in a novel context (cage B). Dialysates were collected every 5 min for 90 min and analyzed by high-performance liquid chromatography. The rats exhibited a significant fear response in cage A but not in cage B. Moreover, increased DA levels in both NAC subregions were observed 5-25 min after the beginning of the test when the animals were tested in the same context compared with accumbal DA levels from rats tested in the different context. These findings suggest that DA mechanisms in both the NAC core and shell may play an important role in the expression of contextual fear memory.     

Dissociation in the involvement of dopaminergic neurons innervating the core and shell subregions of the nucleus accumbens in latent inhibition and affective perception

Mesencephalic dopaminergic neurons have been found to be involved in affective processes. Their implication in cognitive processes appears less well understood. The use of latent inhibition paradigms is a means of studying these kinds of processes. In this study, we investigated the involvement of dopaminergic projections in the core, the dorsomedial shell and the ventromedial shell of the nucleus accumbens, in latent inhibition in olfactory aversive learning. Variations in extracellular dopamine levels induced by an aversively conditioned olfactory stimulus were monitored in the three parts of the nucleus accumbens in the left hemisphere, after pre-exposure to the olfactory stimulus using in vivo voltammetry in freely moving rats. The parallel between dopamine changes and place preference or aversion toward the stimulus were analyzed in pre-exposed and non-pre-exposed animals. Results showed that dopaminergic neurons innervating the nucleus accumbens are differentially involved in the latent inhibition phenomenon. Dopaminergic neurons innervating the core and the dorsomedial shell subregions of the nucleus accumbens appeared to be involved in latent inhibition processes, unlike those reaching the ventromedial shell. Nonetheless dopamine in the ventromedial shell was found to be involved in affective perception of the stimulus.The present data suggest that dopaminergic neurons innervating the three nucleus accumbens subregions are functionally related to networks involved in parallel processing of the cognitive and affective values of environmental information, and that interaction between these systems, at some levels, may lead to a given behavioral output. These data may provide new insights into the pathophysiology of schizophrenic psychoses.     

Impulsivity as a mediating mechanism between early-life adversity and addiction: theoretical comment on Lovic et al. (2011)

Early-life adversity, impulsivity, and dopaminergic function have all been implicated in adult drug addiction. The article by Lovic, Keen, Fletcher, and Fleming in this issue further elucidates this relationship by demonstrating that early-life adversity can increase impulsivity and decrease behavioral flexibility in adulthood. Recent literature suggests that these results are likely due to structural and functional changes in regions such as the orbitofrontal cortex (OFC) and nucleus accumbens (NAc), as well as altered dopamine activity. Impulsivity and behavioral inflexibility can increase susceptibility to addiction, and in turn, chronic substance abuse can impair the neurocircuitry underlying behavioral inhibition. Thus, early-life adversity may act as an entry point into a feed-forward spiral of impulsivity and addiction via the dysfunction of regions such as the OFC, NAc, and mesolimbic dopamine. (PsycINFO Database Record (c) 2011 APA, all rights reserved).     

Impulsivity affects mismatch negativity (MMN) measures of preattentive auditory processing

The current study addresses the relation between impulsive personality and mismatch negativity (MMN) as measure of auditory processing. In a sample of 33 normals, MMN was measured and related to self-reported measures of impulsive behavior. Participants were tested using a passive auditory oddball paradigm while EEG recordings were obtained. It was found that the negative MMN amplitude at the left lateral cluster was negatively correlated with self-reported impulsivity, with high impulsive individuals showing larger MMN amplitudes than low impulsive individuals. This indicates that impulsivity is related to preattentive auditory processing, a process that is not dependent on response execution. In addition to the well-known involvement of top–down control in impulsivity, these findings implicate that the cognitive bottom–up processing of incoming stimuli is associated with individual differences in impulsivity. Since the source of the MMN is thought to be located in the auditory cortex, this suggests involvement of “lower order” temporal lobe processes in impulsive behaviors.     

Noxious heat induces fMRI activation in two anatomically distinct clusters within the nucleus accumbens

Using functional magnetic resonance imaging (fMRI) we found that a noxious thermal stimulus (46 degrees C) to the hand activates the nucleus accumbens (NAc) in humans, while a non-noxious warm stimulus (41 degrees C) does not. Following the noxious stimulus, two distinct foci of decreased activation were observed showing distinct time course profiles. One focus was anterior, superior, and lateral and the second that was more posterior, inferior, and medial. The anatomical segregation may correlate with the functional components of the NAc, i.e., shell and core. The results support heterogeneity of function within the NAc and have implications for the understanding the contribution of NAc function to processing of pain and analgesia.     

Rapid changes in extracellular glutamate induced by natural arousing stimuli and intravenous cocaine in the nucleus accumbens shell and core

Glutamate (Glu) is a major excitatory neurotransmitter, playing a crucial role in the functioning of the nucleus accumbens (NAc), a critical area implicated in somatosensory integration and regulation of motivated behavior. In this study, high-speed amperometry with enzyme-based biosensors was used in freely moving rats to examine changes in extracellular Glu in the NAc shell and core induced by a tone, tail pinch (TP), social interaction with a male conspecific (SI), and intravenous (iv) cocaine (1 mg/kg). To establish the contribution of Glu to electrochemical signal changes, similar recordings were conducted with null (Glu(0)) sensors, which were exposed to the same chemical and physical environment but were insensitive to Glu. TP, SI, and cocaine, but not a tone, induced relatively large and prolonged current increases detected by both Glu and Glu(0) sensors. However, current differentials revealed very rapid, much smaller, and transient increases in extracellular Glu levels, more predominantly in the NAc shell than core. In contrast to monophasic responses with natural stimuli, cocaine induced a biphasic Glu increase in the shell, with a transient peak during the injection and a slower postinjection peak. Therefore, Glu is phasically released in the NAc after exposure to natural arousing stimuli and cocaine; this release is rapid, stimulus dependent, and structure specific, suggesting its role in triggering neural and behavioral activation induced by these stimuli. This study also demonstrates the need for multiple in vitro and in vivo controls to reveal relatively small, highly phasic, and transient fluctuations in Glu levels occurring under behaviorally relevant conditions.     

Impulsivity affects mismatch negativity (MMN) measures of preattentive auditory processing

The current study addresses the relation between impulsive personality and mismatch negativity (MMN) as measure of auditory processing. In a sample of 33 normals, MMN was measured and related to self-reported measures of impulsive behavior. Participants were tested using a passive auditory oddball paradigm while EEG recordings were obtained. It was found that the negative MMN amplitude at the left lateral cluster was negatively correlated with self-reported impulsivity, with high impulsive individuals showing larger MMN amplitudes than low impulsive individuals. This indicates that impulsivity is related to preattentive auditory processing, a process that is not dependent on response execution. In addition to the well-known involvement of top–down control in impulsivity, these findings implicate that the cognitive bottom–up processing of incoming stimuli is associated with individual differences in impulsivity. Since the source of the MMN is thought to be located in the auditory cortex, this suggests involvement of “lower order” temporal lobe processes in impulsive behaviors.