1. Introduction

The brain regions engaged in reward and emotional circuitry overlap and are interconnected in daily operations ^[1]. It is, therefore, only natural to hypothesize that any malfunction in the regions of either circuit is likely to impact both circuits and underlie the comorbidity of emotional disorders and drug addiction ^[2]. Nucleus accumbens (NAc) is one such key region in the brain that is integral to both the reward and the emotional systems involving functions such as motivation, reinforcement learning, pleasure seeking, processing fear or aversive stimuli and initiating motor activity. The aim of the current paper is to provide an in-depth and foundational description of the NAc's structure, connections, and functional role in emotional and substance abuse disorders. This description provides potential explanations for common clinical questions that arise in relation to reward seeking, emotion regulation, and the child development and the impact of associated stimuli. In this regard it is important to understand the structure of the NAc, in the context of the emotional and the reward neural circuitry. This includes the relevant neurochemicals which are dopamine (DA), gamma-aminobutyric acid (GABA), glutamate (Glu), serotonin and noradrenaline, as well as the related neural activity to explain the crucial link between the emotional and substance abuse disorders ^[3].

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2. Basic Neuroscience of NAc

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2.1. NAc connectivity

The connectivity between various parts of the prefrontal cortex, dorsal striatum, ventral striatum, pallidum, amygdala, insula, hippocampus and hypothalamus is depicted in Figure 1. As seen, the NAc is shown in cartoon form to depict the hedonic hotspot (orange) in the rostral region that is responsible for "liking" of rewards based on animal studies. The NAc shell also contains a caudal hedonic coldspot (blue) responsible for "not liking". Similarly, the orange region depicted in the pallidum in the caudal area is responsible for the hedonic hot spot with opioid activity, and suppression in the rostral blue spot. The amygdala is responsible for "wanting", and hypothalamic stimulation leads to an increase in both the "liking" and the "wanting". Dopamine (DA) and glutamate (Glu) are motivating neurotransmitters while gamma amino-butyric acid (GABA) has the effect on lowering the activity. DA is transmitted from ventral tegmental area (VTA) to the NAc and the ventral (Ⅴ) pallidum. DA is also directly transmitted to the dorsal striatum from the VTA. GABA is transmitted from the NAc to the Ⅴ. pallidum, VTA, and lateral hypothalamus. Orexin is transmitted from the lateral hypothalamus to the Ⅴ. pallidum. Glu is transmitted to the NAc from the basolateral nucleus of the amygdala, orbitofrontal cortex, and hippocampus in synchrony with "wanting", valuing, and memories, respectively. The NAc's strong connectivity to insula underlies the visceral sensation of arousal and excitability corresponding to increase in DA and decrease in GABAA.

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2.2. The structure within the NAc of the ventral striatum

The accumbens nucleus or the nucleus accumbens septi (Latin for nucleus adjacent to the septum) is part of the basal ganglia, and is located between the caudate and putamen with no specific demarcation from either caudate or putamen ^[4]. The NAc and the olfactory tubercle together comprise the ventral striatum. It is round in shape with the top portion being flat. The NAc is longer in its rostro-caudal length relative to its dorso-ventral length. It has two components—shell and the core ^[5,6]. The two parts of the NAc share connections and serve distinct and complementary functions.

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2.3. Complementary cellular operations and neurochemical differentiation between the shell and the core

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2.3.1. Shell of the NAc

The outer portion (i.e., the shell) of the NAc is like a hammock on the ventral, lateral and medial sides of the core ^[7,8]. It is part of the extended amygdala, with the amygdala being located rostral to the shell, and sends afferents to the basolateral amygdala. It is a transition zone between the amygdala and the dorsal striatum. The shell also sends afferents to the lateral hypothalamus ^[8].

Neurons in the shell include medium spiny neurons (MSNs). They contain the D1-type or D2-type dopamine (DA) receptors ^[9,10]. In the shell, around 40% of the MSNs express both types of neurons. Furthermore, these neurons have lower density of dendritic spines and less branching and terminal segments compared to the core MSNs. Additionally, serotonin receptors are predominantly located in the shell ^[11,12].

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2.3.2. Core of the NAc

Neurons in the core (i.e., inner part of the NAc) consist of densely placed, highly branched outer cells that are either the D1-type or D2-type dopamine receptors ^[10]. These cells project to the globus pallidus and the substantia nigra.

Enkephalin receptors, which are opioid receptors with enkephalins as ligand responsible for nociception, and GABAA receptors, which bind the GABA molecules to open chloride channels and increase chloride conductance to inhibit new action potentials, are predominantly present in the core ^[13,14].

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2.4. Neurotransmitters underlying the reward, excitement and habituation dopamine-motivation and reward function

Both in the shell and the core, DA action is greater than that in the dorsal striatum ^[15]. NAc is specifically involved in the acquisition of fear response through instrumental conditioning during which animals freeze in the context of aversive stimuli ^[16,17,18]. The NAc core is different from the shell in that it is involved in learning to identify the cues of aversive stimuli in order to avoid them, generalizing to the temporally discrete stimuli. NAc shell is known to define or signal safety periods between aversive cues ^[19,20]. Therefore, when external stimuli are ambiguous or unpredictable, NAc with its dissociable functionality, can aid in avoidance and approach towards intended goal. Therefore, lesions, DA receptor antagonism in the NAc core, or disconnecting inputs from the anterior cingulate cortex to the core, reduce approach toward incentive stimuli ^[21,22,23]. This finding supports the concept that the core plays a key role to "get to the reward". Complementary to this finding, NAc shell is the key region responsible for suppressing irrelevant, non-rewarding, and less profitable actions to help "stay on task". Evidence points to the fact that any lesion to the NAc shell leads to uninhibited approach to the reward with less discretion ^[24]. Also, while high density of transporters renders greater utility of DA in the core, drug induced serotonin and DA antagonism (e.g., clozapine, a treatment for psychosis) leads to greater DA turnover in the shell. Indeed, the shell is the main region of the anti-psychotic action based on corresponding mRNA activity within the shell ^[25,26]. Appetitive, addictive, excitable, and psychotic behaviors are associated with high levels of DA. High levels of amphetamine will increase DA to equal levels in the extracellular space of the shell and the core ^[27]. Such an increase in DA due to psychostimulant administration for attention deficit hyperactivity (ADHD) can lead to excitability and mania, psychosis, or more intense drug seeking among vulnerable individuals prone to these illnesses ^[28,29]. While we understand the clinical phenomena of such occurrences, it remains unclear as to what makes subgroups of individuals prone to such instability with DA administration. Non-drug rewards are also known to increase DA, specifically in the NAc shell, leading to habituation ^[30,31]. Furthermore, repeated drug induced stimuli and corresponding increase in DA lead to more pernicious habituation in those individuals relative to repeated non-drug related rewards and DA spikes ^[32]. The possibility that non-drug related rewards could cause DA spikes and habituation may explain the concept of video game addiction, establishing the neural correlates of addiction.

Furthermore, the NAc is a key structure in motivation, emotion regulation and impulse control. With regards to reward seeking and impulsive judgments, both the lesion studies of the NAc in animals and functional imaging studies in gambling have implicated ventral striatum abnormalities as leading to impaired intertemporal choice, risk-taking, or impulsive behaviors in tasks involving options with probability differences. Impulsivity may have many causes, but the NAc is one such channel implicated in reward and emotion regulation ^[33].

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2.5. Dopamine and glucocorticoid receptors-role in mental excitability and potential psychosis

DA and glucocorticoid receptors are present in the NAc shell ^[34,35]. Excessive steroids or DA in the NAc, lead to psychosis. Glucocorticoid receptors enhance the DA release and related activity ^[35,36], potentially inciting psychosis. Additionally, epigenetic changes, such as DNA methylation of the glucocorticoid receptor gene (NR3C1) due to traumatic events, are particularly present in adolescence ^[37,38].

Therefore, stress, as well as dopamine increase associated with psychostimulants or drugs of abuse, can precipitate psychosis through interrelated mechanisms in the NAc. Additionally, the NAc receives direct projections from the hippocampus and the basolateral amygdala. When there is a lesion in NAc and/or the stria terminalis pathway that connects to the amygdala, glucocorticoid agonists cannot enhance and modulate memory consolidation ^[39]. Therefore, dopamine abnormalities leading to psychosis or early adversity may lead to co-occurring cognitive problems, such as those related to memory.

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2.6. GABA and glutamate-moderate motoric excitability

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2.6.1. GABA

If GABAA is low in the NAc, it leads to hyperactivity or excitability, and the reverse is true for hypoactivity ^[12,40,41]. This may have pharmacological value where DA induced hyperactivity can be reduced by GABAA by way of the NAc connections to Ⅴ. pallidum (i.e., external segment of the globus pallidus of the basal ganglia in the subcortex) that influences motor activity ^[42]. Based on the insula's role in processing visceral sensation of arousal ^[43,44], the NAc's strong connectivity to the insula can explain the physiological arousal associated with DA increase and GABAA decrease or vice versa ^[45,46]. The GABAB receptors also inhibit locomotion, but are mediated by acetylcholine (ACh) ^[45,47].

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2.6.2. Glutamate

This neurotransmitter has parallel, but the opposite effect, of GABAA via the NAc ^[48]. It has been shown that locomotor activity or motoric excitability is not contingent on DA activity alone, but is also based on the NAc activity involving GABA and glutamate ^[49,50]. It was recently demonstrated through animal studies that the motoric decision to reach for reward is not initiated in the NAc, but is facilitated through efficiency in motor action selection while approaching the reward ^[51].

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2.7. Acetylcholine (ACh) and its role in reward system

Striatal muscarinic ACh interneurons include M1, M2, and M4; M1 is post-synaptic and excitatory, whereas M2 and M4 are pre-synaptic and inhibitory. These interneurons synapse with GABA mediated spiny output neurons. The NAc, central to the motivations and reward behaviors that underlie drug addiction, projects ACh output neurons to the Ⅴ. pallidium. Preclinical studies showed that ACh from the NAc mediates reinforcement through its effect on reward, satiation, and aversion, and chronic cocaine administration has shown neuroadaptive changes in the NAc. ACh is further involved in the acquisition of conditional associations and drug seeking behavior through its effects on arousal and attention. Long-term drug use was shown to cause neuronal alterations in the brain that affect the ACh system and impair executive functions. As such, it may contribute to impaired decision making that characterize this population and may exacerbate the risk of relapse during recovery ^[52]. In addition to its interface with the GABAB receptors in inhibiting locomotion, ACh is also responsible for satiety after feeding, and reduced levels are associated with bulimia like feed-purge cycles ^[53]. Therefore, ACh has a role in indirectly moderating the reward circuit.

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2.8. Connective dynamics of the interfacing reward and emotional circuitry regions involving the NAc: The basis for emotion regulation and habit formation

Disorders involving mood and substance abuse often coexist. Factors that appear to be involved include those related to overt affective processing, motivation, and impaired decision-making. To understand the habit formation, to the first step begins with the reward system's modus operandi. The dorsal and ventral regions of the striatum work in complementary fashion. The dorsal striatum is central to learning the contingencies of the reward stimulus, and entraining the instrumental conditioning ^[54,55]. In other words, the dorsal striatum optimizes the reward related action-choice. Subsequently, it is the NAc in the ventral striatum that is responsible for the subsequent outcome based predictions ^[56]. The NAc predicts the error-based outcome and updates the predictions of reward or punishment ^[57,58]. The mesolimbic neurons of the ventral tegmental area (VTA) synthesize DA and the substantia nigra sends the DA predominantly to the shell and the core of the NAc, to allow it to perform its functions ^[59,60]. It is the incoming signals from the frontal lobe and the amygdala, modulated by DA, that biases the behavior towards reward ^[61,62]. Search behavior is facilitated by the connections between the hippocampus and the NAc shell, especially if there is ambiguity and lack of clear direction towards reward ^[1].

Additionally, the lateral hypothalamus, that is involved in regulatory activities (e.g., the "feeding center") sends signals through mesocorticolimbic projections to NAc and the Ⅴ. pallidum ^[63]. It appears the NAc and the Ⅴ. pallidum serve as hedonic hotspots for "liking" and motivational function of "wanting" rewards ^[64,65]. The mu opioids and the DA receptors in the shell of NAc and the Ⅴ. pallidum specifically serve in "liking" and "wanting" functions ^[66,67]. The DA levels in the NAc and the norepinephrine released at locus coeruleus in the brain stem play a critical role in addiction, specifically in drug seeking when deprived of the habituated drug ^[68,69].

Additionally, the dopaminergic neurons from the VTA that innervate the olfactory tubercle, part of the striatum next to the NAc ^[69], and are involved in mediating the rewarding effects of drugs such as amphetamine by generating arousal. Therefore, while the initial learning of pleasure and associated contingencies occur through dorsal fronto-striatal circuitry, it is the ventral reward system of the orbitofrontal cortex (OFC), striatum, and pallidum that maintains the cycle of habituation ^[70].

Furthermore, input from the glutamatergic neurons of the amygdala, hippocampus, thalamus and prefrontal cortex (PFC) to the NAc facilitate the synchrony between the "liking" and the "wanting" ^[71]. More specifically, glutametergic projections from the OFC and ventromedial PFC to the NAc shell are known to strengthen the reward seeking ^[72,73]. Therefore, the amygdala and the OFC can be viewed as conveying the "want and need" or the opposite state of "not wanting or aversion". It is the NAc that sets the tone for the motivational significance or appreciation in the case of feeding or any other pleasurable activity (i.e., "liking" or "not liking").

The amygdala sends the affective signals that are conducive to the desire for the drug ^[74,75]. The hippocampus is responsible for storing memories associated with past drug use and associated pleasure ^[75,76]. The insula provides the aspect of the bodily experiences of pleasure and arousal state related to the drug intake ^[77]. Relative value of the reward and associated outcome-guided behavior is determined by the OFC, both in relation to the rewarding stimulus or, in the case of devaluation of the stimulus, cessation of the seeking behaviors ^[61].

Overall, output from the NAc extends to the regions of the basal ganglia, amygdala, hypothalamus and the PFC regions. Based on neuroimaging studies involving healthy controls (HC), mood disordered subjects, and substance abuse subjects, medial prefrontal cortex (MPFC), anterior cingulate cortex (ACC), ventrolateral prefrontal cortex (VLPFC) and precuneus emerged as hubs in the interlinked reward and emotion circuitries. Impulsive and compulsive drug seeking behaviors are moderated both by nature and nurture. The genetics behind disorders of impulse control and addiction serves to explain the physiological predisposition, while the environmental influencing factors (e.g., parental restrictions or peer pressure in drug usage) may limit or expand the exposure and actively contribute to entraining the habit circuitry.

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3. Clinical Neuroscience of NAc

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3.1. Nucleus Accumbens' role in the hot mess of emotion dysregulation and addiction

The predominant activation pattern is depicted in Figure 2. This shows patient groups in each of the disorders in comparison to healthy controls with tasks probing either reward or emotion neural circuitry. The arrows represent an increase or a decrease in activation in the key regions of the reward and the emotion circuitry that are intricately connected. In the case of bipolar disorder (BD), the NAc shows increased activation in response to emotional stimuli and decreased activation in response to rewards, the latter pattern being similar to that seen in major depressive disorder (MDD). In MDD, the NAc shows decreased activation to both emotional stimuli and reward, opposite to that observed in substance abuse disorder.

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3.2. Neural pattern of activation in the NAc in substance abuse and mood disorders: human imaging studies of emotional and reward stimuli

Most of the human studies that extended the knowledge on the role of the NAc are based on fMRI studies probing the reward and/or emotional circuitry. In relation to the NAc, the most accurate view is obtained as T2 images and in the coronal section where it is the longest and shows the most detail ^[3]. A consistent pattern of brain activation has emerged in identifying the interfacing circuitry dysfunction across the disorders. In the interpretation of these experiments, both increased activity and the absence of activity must be considered. When there is stimulus of moderate intensity, brain region that is partially operating even if impaired, shows increased activation. If the same brain region is probed with stimulus of severe intensity (also mediated by the type of the disorder where perceptions vary, such as patients with bipolar disorder react to angry faces more than fearful faces), it would show no activation or decreased activation relative to healthy population. This phenomenon has been noted on careful examination of the patterns over multiple studies to make sense of the variability in brain activation in response to varying probes.

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3.2.1. Major depressive disorder (MDD)

Relative to that of HC, the individuals with MDD showed decreased activation in the NAc in response to any rewarding stimuli, but increased activation to implicit emotional stimuli (e.g., covert face processing or cognitive generation of positive affect) ^[78]. In other words, in MDD, the NAc is underactive with reward and this may explain why this population appears to need larger reward to attain the same level of activation as HC (i.e., "not easily pleased") An alternative physiological explanation is that the reward stimuli may serve as explicit emotional triggers in depression, with lower impact on activating the NAc. Hence, it may be that incidental or implicit emotional stimuli trigger the excessive reactivity in the NAc. Corresponding to the NAc activity, the amygdala also shows increased activation in the MDD patients, relative to HC, in response to negative or implicit emotional stimuli ^[79]. The various prefrontal regions show variable patterns of either increased or decreased activation, unlike the consistent pattern noted in the subcortical areas ^[80,81]. Within our clinical experience excessive use of substances appears to have the purpose of self-medicating to subdue negative emotional states associated with a lowered threshold for reactivity to negative triggers. This corresponds with the physiological experiments we have summarized.

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3.2.2. Bipolar disorder (BD)

In response to reward task and regardless of comorbid substance abuse, relative to HC patients with BD show lower activation of the VLPFC and increased activation of the amygdala for implicit or explicit negative emotions, in addition to compensatory over activation of the ACC ^[82]. A fascinating observation is that the NAc behaves in the exact manner as the VLPFC; implicit negative affective processing leads to decreased activation, while both implicit and explicit happy or fearful faces lead to increased activation ^[83]. One notable point is that, in BD, sad or angry emotions tend to be more directly relevant than fear as negative emotional stimuli, which can explain the increased activation associated with fear. Therefore, when emotional tasks are used to activate the emotion circuitry, the intensity of the tasks appears to proportionally trigger a dysfunctional under-activation in the VLPFC of BD subjects relative to the HC. This gives the appearance, that the VLPFC "gives up" in response to severe or intense negative emotions.

In response to reward anticipation, the NAc showed decreased activation in response to monetary reward in BD subjects relative to HC ^[84]. This is a pattern similar to that seen in MDD, suggesting the need for greater reward to obtain the same emotional impact as in HC. Thus, the pattern in BD differs from MDD in response to emotional stimuli based on pathophysiological differences, though leading to a similar behavioral response to the reward stimuli.

In explanation as to what could underlie clinical scenarios in BD, the physiological findings of the neuroimaging experiments complement the knowledge derived from animal studies. In this regard, it is possible that increased amygdala activity in BD projects a certain degree of intensity corresponding to the excitability. The decreased activity in the VLPFC and OFC regions may lead to disinhibition, and associated poor impulse control, and result in excessive pleasure seeking related to impairment in PFC-mediated decision-making. Based on animal studies ^[85] and BD human neuroimaging studies ^[86], connectivity between the amygdala and the NAc may be relevant in accentuating the "want" and the "like" in seeking rewards. Therefore, the intense reward-seeking behaviors (e.g., excessive shopping, drug use, food consumption, or sex) may be due to the interlinked dysfunction in the emotional and reward systems.

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3.2.3. Substance Abuse Disorders

In addiction or substance abuse disorders, relative to HC, passive or implicit perception of craving-related stimuli leads to increased activation in the NAc ^[87]. This underlies the motivation bias associated with increased activation in the OFC, ACC, and amygdala, the regions that are linked to both reward and emotional circuitry ^[87]. These regions appear common to all reward seeking, regardless if the stimuli are or are not drugs ^[88,89]. While motivation toward seeking goals is dependent on the NAc in the ventral striatum, the progressive shift to habit formation appears dependent on the dorsal striatum ^[90]. This is in correspondence to the "liking" hypothesis in which with the initial observation of the reward is associated with NAc activation. In substance use disorders, relative to HC, decreased NAc activation occurs in this anticipatory observational phase, regardless of any subsequent loss or gain of a reward ^[91]. Increased DA release in the anterior ventral striatum, but not in the dorsal caudate, was shown to be positively correlated with the hedonic, or "liking", response to dextroamphetamine ^[92]. In actuality, the positive affective experience of hedonic "liking" is not readily disentangled from "wanting" the drug ^[93]. Related to depression, seeking a hedonic response is a possible explanation of self-medicating through abuse of drugs. Similarly, stimulant use in a subpopulation of users may be primed due to seeking excessive rewards that is triggered by excessive dopamine.

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3.2.4. Treatment implications through deep brain stimulation (DBS)

The DBS of the NAc was attempted for the treatment refractory obsessive-compulsive disorder where compulsion was considered to be similar to that of drug-seeking compulsivity, involuntary motor activity like Tourette syndrome, depression and drug and alcohol abuse ^[94]. All these attempts yielded no conclusive findings on outcome. Symptoms of depression were reduced by approximately 40% in this cohort ^[94,95].

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3.2.5. Placebo effect in healthy individuals

When healthy adults were given a pain challenge, DA and opioid activity in the NAc were associated with subjectively perceived effectiveness of the placebo based on reductions in pain ratings ^[96]. Similar to reward expectation, this supports the NAc's involvement with anticipation of a positive response.

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4. Summary and Conclusions

The foregoing discussion had the goal of providing an in-depth analysis of the NAc to allow scientists and educators to be aware of multiple aspects of its functionality. In relation to functional imaging, identifying the NAc requires careful analysis due to the multiple, small adjacent regions, such as parts of the caudate and putamen, that could be mistaken for the NAc or vice versa. With this in mind, the shape of the NAc means the best view is accomplished in the coronal section in interpreting the neuroimaging findings. Additionally, an understanding of the role of the NAc in a systems perspective of emotional and reward circuitry offers a broader perspective of its role in brain operations. The current paper has presented findings on the NAc from both human and non-human animal studies, with an examination of those findings as related to a clinical understanding. The existing scientific literature of both the basic and the clinical neuroscience paired with the acumen from clinical insights align a powerful triad toward translation to advance our understanding of the NAc's functional role, as has hopefully been illustrated in this manuscript. In summary, the clinically applicable derivatives of neuroscience, where the NAc plays a key role, are as follows:

1. The NAc plays a significant part in channeling DA, GABA and glutamate in modulating the reward and emotional systems.

2. Dissociable roles of the NAc core and the shell involve selecting the reward and evading distractions, respectively.

3. The NAc shows decreased activation to reward in individuals with MDD and BD, relative to that HC, and this can potentially explain the lack of pleasure with reward (akin to anhedonia) in MDD and the need for intense pursuit of reward in BD.

4. While the NAc shows increased activity in all substance use disorders, relative to HC, animal studies indicate joint increase in activity in the highly connected amygdala and Ⅴ. pallidum. Anticipating and selecting reward with NAc involvement from human studies and the amygdala's excitability to accentuate the reward seeking in animal studies, can together inform the emotional overlay in addictive behavior.

5. It is also possible that inattention and impulse control associated with low DA or noradrenaline levels may lead to poor frustration tolerance, and potentially, seek reward as gratifying alternative. In this scenario, optimal treatment with psychostimulants could avoid being habituated to illicit drugs. It appears that adolescence is particularly a vulnerable time for the precipitation of any illness with accentuated glucocorticoid receptor sensitivity in the NAc. While there are no definitive answers, these unanswered questions pose research challenges for the future.

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Conflict of Interest

All authors declare no conflicts of interest pertaining to this paper.

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