Journal of Addiction Research & Therapy
Open Access

Drug addiction; Psychodynamics; Compulsion; Healthcare

Introduction

Drug addiction represents a pressing global challenge in contemporary society, with approximately 243 million people worldwide grappling with substance abuse. This issue is accompanied by escalating societal costs, including increased healthcare expenditures, diminished productivity, and a surge in crime rates. The core symptom of drug addiction lies in compulsive drug use behavior, where individuals persistently seek and consume drugs despite severe negative consequences. Indeed, in the American Psychiatric Association's Fifth Edition of the "Diagnostic and Statistical Manual of Mental Disorders" (DSM-5), the diagnosis of substance use disorder emphasizes the compulsive features exhibited by individuals, such as spending significant time and money seeking drugs, neglecting essential life activities (e.g., employment and basic social interactions), and persisting in drug use despite experiencing adverse physical and psychological effects. However, a key issue in addiction is that not everyone transitions from recreational, controlled drug use to uncontrolled, compulsive drug use. Only a small minority, approximately 15%-20% of individuals, cannot flexibly adjust their behavior. This implies that there are significant individual differences in the process of transitioning towards addiction. Susceptibility factors propel individuals from initial drug use to maintenance and the development of addiction. Recognizing these susceptibility factors is crucial for addiction prevention. However, there is currently no consensus, and two classic theories have emerged in the understanding of addiction: the opponent-process theory and the incentivesensitization theory. The opponent-process theory posits that individuals initially experience the pleasurable effects of drug use (positive reinforcement). However, as tolerance, anxiety, and negative effects emerge, they experience relief from drug withdrawal symptoms (negative reinforcement). In summary, the opponent-process theory suggests that addiction involves drug choices driven by negative states. However, this theory does not account for individual differences in addiction and cannot explain why individuals may exhibit strong drug motivations even when they are not in a withdrawal state. The incentivesensitization theory provides a reasonable explanation for individual differences in addiction. According to this theory, addictive substances induce adaptive changes in the nervous system. These changes do not alter the pleasurable experience of the drug ("liking" the drug) but instead grant drug-related cues a strong motivational significance ("wanting" the drug). The incentive-sensitization theory successfully explains the separation of actions and intentions reported by many addicts and the fact that even after extended periods of abstinence, subtle environmental cues can trigger intense drug cravings. Individual differences in addiction stem from varying attributions, with the core characteristic of individual addiction being the attribution of reward to drug-related cues. The phenotypes of Sign-trackers (ST) and Goaltrackers (GT) observed in the classic Pavlovian conditioned approach (PCA) paradigm, as well as the strong Pavlovian-instrumental transfer (PIT) effects displayed by ST in the PIT paradigm, align perfectly with the incentive-sensitization theory. In PCA, neutral stimuli (e.g., a bell) repeatedly paired with unconditioned [1 -8] stimuli (US, e.g., food) become conditioned stimuli (CS), leading to conditioned responses (CR) in rodents. ST, as cue responders in the PCA, exhibit a stronger incentive quality for cues predicting rewards (e.g., lever press). They tend to approach these cues initially, and this cue's incentive can even persist in the absence of the US. GT, as goal responders, are less sensitive to cues predicting rewards. For instance, they may initially approach the food trough when it suggests a reward is available and do not invest as much time and effort in cue-related cues (Figure 1). In the PIT tests, ST individuals exhibit greater transfer effects, further highlighting the significant incentive value of CS for ST. As mentioned in the incentive-sensitization theory, this pathological incentive for cues may indeed be a driver of addiction. Correspondingly, research has reported that, compared to GT, ST individuals are more likely to predict compulsive drug use behavior in addiction. According to the 3-CRIT for judging compulsive drug use in animal models: (1) resistance to punishment (such as shock) during continued drug responses, (2) continued responses (drug craving) when the drug is unavailable, and (3) motivation to seek the drug under progressive ratio schedules. Research findings indeed suggest that when subjected to relevant tests, ST individuals exhibit features of compulsion as outlined in the 3-CRIT criteria. Despite reports of contradictory results, when the CS is devalued (CS associated with an aversive stimulus, such as lithium chloride), ST individuals do exhibit reduced responses to CS. However, this may be context-dependent, as ST can lose sensitivity to CS devaluation when the contextual environment is inconsistent, subsequently reverting to compulsive seeking. This aligns with realworld scenarios, such as the effectiveness of addiction treatment in controlled settings but susceptibility to cue-induced relapse in daily life. Furthermore, ST and drug abuse share common neural foundations. Thus, the potential differences between ST and GT phenotypes may indeed be related to individual variations in addiction. Another pivotal question revolves around whether these two phenotypes observed in animal models exhibit consistent or analogous patterns in humans. This consideration affects the potential for the susceptibility demonstrated within the ST phenotype to hold relevance for human translation. Previous research suggests that such a translation is not only possible but also reasonable. In human studies, akin to findings in animal models, both ST and GT phenotypes have been identified. While intermediate types also exist (in line with animal models), a predominant bimodal distribution trend has emerged in human populations (Figures 2-4). Moreover, investigations employing eye-tracking and functional magnetic resonance imaging (fMRI) techniques have provided evidence of distinct neural mechanisms for ST and GT in humans. Some researchers have commented on the applicability of analogizing ST traits to humans. Similarly, studies have indicated that in humans, individuals who exhibit a focus on cues akin to ST may also be associated with more severe addiction and compulsivity. In summary, it is appropriate to translate ST and GT from animal models to human research. Moreover, the behavioral characteristics exhibited in ST can help [9 -15] in understanding susceptibility factors in human addiction. There is increasing evidence that substance addiction is associated with habitual behavioral patterns. Therefore, in many studies, the behavioral characteristics of ST are referred to as "model-free" habitual behavioral patterns, while GT represents "model-based" goal-directed behaviors. Second-order schedules can be used to investigate drug-related cue-reinforced seeking responses, such as studying the transition from goal-directed to habitual seeking controlled by CS in substances like heroin, cocaine, and alcohol. However, current research often conflates cue incentive sensitization and habituation within ST as the same process. This review argues that these two phenomena are not equivalent and are distinct in both psychological processes and neural foundations. In ST, cue sensitization remains goal-directed behavior, determined by the high incentive value of cues. This excessive attention to cues may be related to attentional bias and reflect poor attentional control in individuals. Its neural basis may be associated with dopamine neurons projecting from the ventral tegmental area (VTA) and substantia nigra compacta (SNc) to forebrain targets like the nucleus accumbens (NAc), encoding motivational behaviors. The habituation within ST is related to a weakening of behavioral inhibition in individuals, reflecting a lack of planning in behavior. For example, compared to GT, ST individuals exhibit earlier and more frequent lever-pressing behavior. This pattern of weakened inhibition primarily manifests as difficulties in top-down control, potentially associated with deficits in cholinergic modulation in the cortex, the gradual waning of cortical control over subcortical structures, and the shift from the ventral to dorsal striatum (from ventral striatum (VTS) and dorsal medial striatum (DMS) to dorsal lateral striatum (DLS)). It is worth noting the synaptic plasticity between the cortex and striatum, which is linked to the Dopaminergic neuronal projection from the midbrain to nucleus accumbens medium spiny neurons (MSN). This further emphasizes that learning associated with high-incentive cue associations may form the foundation for the transition to habitual behaviors. The failure of goal-directed control and the dominance of habitual behavior patterns may serve as the basis for the shift from controlled drug use to compulsive drug use. Hence, the behavioral characteristics, underlying factors, and biological basis exhibited by ST seem to shed light on individual differences in human addiction. First, concerning behavioral characteristics, as mentioned earlier, ST individuals are more prone to cue sensitization, which may be associated with attentional biases. Conversely, habituation may be linked to poorer behavioral inhibition, a trait often found in individuals with impulsivity. Individuals with high impulsivity traits often exhibit reduced attentional capacity and behavioral inhibition, which has been associated with impulsive behaviors and various substance use disorders in human studies. It is worth noting that, in terms of impulsive choice, there is no difference between ST and GT, suggesting that ST may only demonstrate poor behavioral inhibition without necessarily being sensitive to issues of time or probability discounting. Furthermore, the use of selectively bred High-Responder (BHR) and Low-Responder (LHR) rats has shown differences in incentive attribution, with BHR primarily showing ST characteristics. This implies that novelty-seeking traits may be susceptibility factors for addiction. There is already considerable evidence linking noveltyseeking personality traits to substance addiction, including nicotine and cocaine. Secondly, the driving role of psychodynamics in ST is noteworthy. In humans, substance abuse or addiction is often associated with a range of other behavioral syndromes collectively referred to as "externalizing disorders," which includes impulsivity. These "externalizing disorders" are linked to early-life environmental stress, developmental experiences, and attachment relationships (typically with caregivers), with positive parenting being a protective factor against these disorders. In summary, this review explores susceptibility factors in the transition from occasional, recreational drug use to uncontrolled compulsive drug use from three interrelated levels: personality traits, psychodynamics, and neurobiology.

Figure 1: Sign-trackers and goal-trackers in rodents. a. Sign-tracker: responsive to cues, rats display an interest in the lever, akin to the us (food), by approaching and nibbling on the lever. b. Goal-tracker: focused on the goal, these rats show no interest in the cues and consistently approach the reward immediately after cue presentation.

Figure 2: Distribution of sign-trackers and goal-trackers in human and animal studies. a. In rodents, sign-trackers and goal-trackers exhibit a nearly symmetrical distribution. b. In human studies, sign-trackers and goal-trackers display a proportion similar to that observed in animal research.

Figure 3: Predominant Neuronal Type in the NAc. In the striatum, approximately 95% of neurons are of the Medium Spiny Neuron (MSN) type, characterized by GABA as their primary neurotransmitter. The dendritic spines on MSN neurons resemble antennae and serve as sites for information exchange between glutamatergic neurons from the cortex and dopaminergic neurons from the midbrain.

Figure 4: Failure to disengage from the dorsolateral striatum (DLS) reflects the compulsivity of addiction. In native rats, individuals typically maintain a balance between goal-directed and habitual behaviors. However, during drug exposure, those individuals dominated by the DLS gradually transition towards compulsivity.

Compulsivity driven by personality traits

Novelty seeking

Novelty seeking refers to the tendency to initiate behavior in response to new stimuli and potential rewards. This trait was initially introduced as part of the biopsychosocial model proposed by Cloninger and colleagues in 1993. This model is based on complex interactions among genetics, psychology, social influences, culture, and spiritual dimensions, categorizing an individual's personality traits into two major aspects: temperament and character, consisting of a total of seven sub-dimensions. Cloninger posited that novelty seeking is a component of an individual's temperament module, representing a non-learned instinctual behavior characterized by a high motivation for new stimuli in the environment. As mentioned earlier, selectively bred rats that exhibit different responses to novel stimuli also show differences in attribution to incentives. Rats with high noveltyseeking tendencies often display ST in PCA, suggesting that the novelty-seeking trait might be one of the susceptibility factors in the transition to compulsive behaviors. However, research on novelty seeking in addiction has yielded mixed results. In human studies, the novelty-seeking trait can predict susceptibility in the initial stages of self-administration and compulsive drug use. Novelty-seeking levels measured in early adulthood can serve as predictive factors for the abuse of substances such as alcohol, nicotine, cannabis, and various other substances. But another animal study that aligns with the 3-CRIT suggested that the high novelty-seeking phenotype cannot predict binge-like drinking behavior in mice. It's worth noting that Belin et al.'s research may reveal a complex structure of the novelty-seeking trait, with its different dimensions being related to different aspects of addiction. As defined by Zuckerman and others, novelty seeking is "a personality trait characterized by a tendency to actively seek out new and exciting sensations, and a willingness to take physical, social, legal, and other risks for the sake of experiencing these novel sensations. Questionnaire measurements of novelty-seeking traits in human studies also encompass dimensions such as impulsivity, exploratory excitement, and disorderliness. Therefore, novelty-seeking measured in animal models may not capture all the features of human noveltyseeking, which could be a reason for the inconsistencies between human and animal research findings. This notion is supported by studies that investigate subtypes of novelty-seeking. Researchers have further subdivided high novelty-preferring rats (BHR) into high novelty preference (HNP) and low novelty preference (LNP) subtypes based on their choice preference in free-choice procedures. The results suggest that HNP may be a susceptibility factor for compulsive cocaine use, promoting the transition from cocaine use to compulsive behavior. These findings indicate that making fine distinctions in animal models may help us better understand the mechanisms underlying compulsive drug use in addiction. Novelty-seeking may predict the transition from drug use to compulsive behavior due to two potential factors. From a neural mechanism perspective, novelty-seeking and sensitization in ST may share a common biological basis. For example, many addictive drugs lead to an increase in dopamine levels in the mesolimbic system. Alcohol has complex effects on gamma-aminobutyric acid (GABA) and glutamate receptors, resulting in rapid changes in dopamine levels in the NAc. Cocaine, as a potent stimulant, increases dopamine levels by blocking the reuptake of dopamine at neuronal terminals, while nicotine can directly depolarize dopamine neurons. Among the neurotransmitters associated with substance addiction, some have also been reported in studies related to novelty-seeking behavior. For example, Rohan et al. revealed that exposure to a new environment could activate neural pathways shared with addiction. Behaviorally, novelty-seeking may encompass characteristics such as poor attention and impulsivity, all of which fall under the concept of behavioral inhibition. These traits may include compulsive cue-seeking behavior seen in ST.

The trait of impulsivity

The trait of impulsivity is a complex, multidimensional construct that can conceptually be divided into two main components: impulsive behavior and impulsive choice. High impulsivity has been associated with a range of psychiatric disorders, including bipolar disorder, attention-deficit/hyperactivity disorder, and borderline personality disorder, among others. Within the realm of personality traits, impulsivity is generally defined as "the tendency to make rapid, unplanned, or reward-driven responses to internal or external stimuli without adequately considering the potential consequences for oneself and others. The description of the impulsivity trait in humans aligns with the characteristics of ST. As previously discussed, we distinguished between sensitization and habituation in the formation of ST behavior, which is consistent with the attention deficits and lack of planning features observed in human impulsivity traits. Firstly, there's sensitization. ST attributes the incentive value to cues rather than drugs, and even when the reward is lost (e.g., food), it cannot stop the attention to cues. For example, raccoons may become fixated on biting coins (US) and miss out on food (CS) rewards. Attention control deficits may be related to this behavioral pattern. For example, ST typically perform poorly in sustained attention tasks (SAT). The attention capture related to cue rewards may form the basis for incentive attribution, and this cue sensitization may predict compulsive behavior in addiction. In human studies, cue-reward-related attention capture has been found to predict an individual's addiction and compulsive behavior, and is associated with the severity of compulsive behavior. This attention bias may be the basis for cognitive inflexibility patterns. Compulsive behavior can be understood as a focus on the immediate action despite adverse consequences, losing the association between behavior and consequences. Attentional narrowing may be a precursor to transitioning to these compulsive traits, but at this stage, it is still goal-oriented. Therefore, the core features of compulsive use in addiction are the excessive habitual behavior (lack of planning) following cue sensitization and the inability to break free from habitbased control during drug use (Figure 4). Habitual behavior is based on stimulus-response associations and typically occurs after extensive training. Once habits are established, they require fewer cognitive resources, making the response often independent of outcome value, triggered by specific cues or stimuli (automatic attention to cues). The reduced capacity for top-down behavioral inhibition observed in ST may make it more prone to habit formation. In other words, in the competition between goal-directed and habitual behavioral patterns, ST individuals may be more inclined to have their behavior dominated by habit-based patterns. Therefore, the impulsivity trait, characterized by impulsiveness or a lack of goal-directedness, may link habit formation with compulsive drug-taking behavior. It is this deficient top-down control that makes it difficult to quit drug use and shift back to goal-directed behavior. Normally, when there is reward devaluation, individuals quickly revert to goal-directed behavior. However, individuals with high impulsivity traits, due to poor attention control and weakened top-down behavioral inhibition, are prone to remain sensitized to cues, maintaining habitual attention to cues and subsequent behavioral responses. In drug use, this habit-dominated behavioral pattern leads to the transition to compulsive drug-taking and eventually evolves into uncontrolled drug-seeking behavior.

Psychodynamics in addiction

High impulsivity and addiction both fall under the category of externalizing disorders, and the development of such externalizing disorders is influenced by an individual's early life experiences. Therefore, to further understand the origins of impulsivity, attention deficits, and novelty-seeking behavior, we will delve into the psychodynamic perspective to comprehend the psychological processes involved in the transition towards compulsive drug use during an individual's drug use development. Adverse experiences, the establishment of attachment relationships, and exposure to stress during an individual's early developmental stages may influence susceptibility to compulsive behavior in addiction. It's important to note that these adverse experiences, attachment, and stress are not isolated factors; they often interconnect and mutually affect each other. For instance, early separation from caregivers during childhood is both an adverse experience and an example of an insecure attachment relationship. While these factors overlap, they also have distinctions. For instance, early adverse experiences may be related to the dopamine neural system, attachment relationships emphasize social interactions and may be related to the oxytocin system, and stress may be associated with an individual's hypothalamic-pituitary-adrenal (HPA) axis function.

Early adverse experiences

Early adverse experiences in rodents are typically characterized by disrupted caregiving behaviors, such as premature separation from the mother. Research has shown that animals experiencing such adverse experiences tend to exhibit high novelty-seeking behaviors in adulthood, consistent with what was mentioned earlier. In addition to showing high seeking traits, they also demonstrate greater sensitivity to addictive substances. These early adverse experiences may physiologically impact the activity of dopamine neurons in the brain. For instance, adolescent rats exposed to early maternal separation exhibit alterations in baseline dopamine levels in the striatum and prefrontal cortex. Importantly, there are also changes in the levels of dopamine release induced by stimuli. For instance, an enhanced dopamine release in response to rewarding stimuli has been observed in the VST and hypothalamus. The altered patterns of reward and motivation-related brain dopamine neuron activity resulting from these early adverse experiences have also been consistently observed in human research. These changes in dopamine neuron activity patterns may be related to the attribution of incentive to subsequent drugrelated cues. Additionally, early adverse experiences can lead to the development of compulsive behavioral traits during adolescence. All of these findings suggest that early adverse experiences in individuals may drive drug use behaviors in addiction towards compulsivity.

Attachment relationships

Secure attachment relationships have a protective effect against substance abuse in adulthood. The positive social interactions between individuals and their caregivers contribute to the development of executive functions and self-regulation. In contrast, a lack of soothing and positive attachment experiences can hinder the establishment of these functions, eventually manifesting as impulsive traits, particularly attention deficits and weakened behavioral inhibition within an individual's personality. For instance, rodent models have demonstrated that rats with insufficient early social interaction experiences (poor attachment experiences) exhibit significant arousal towards reward-related cues, leading to a loss of behavioral inhibition. On the other hand, the HPA axis is believed to directly influence the behavior of ST and GT within the PCA, with ST showing greater cortisol release during single PCA sessions. However, positive social interaction experiences can reduce HPA axis activity, inhibiting ST's seeking responses to cues within the PCA. Recent research suggests that attachment and addiction may share a common neural basis. Therefore, individuals with maladaptive attachment relationships may have their neural systems perpetuating the development of addictive behaviors.

Stress

Early life stress events can lead to maladaptive tendencies, such as children facing extremely harsh parenting styles often exhibiting higher levels of impulse control disorders and externalizing disorders. In rodent studies, rats subjected to stress due to social isolation exhibited more cue-induced sensitization characteristics and showed heightened locomotor reactivity to novel stimuli during adolescence. Furthermore, the HPA axis is involved in a series of cascading neurotransmitter and hormone regulatory processes related to stress. In chronic stress environments, sustained activation of the HPA axis can enhance extracellular DA release in the striatum, indirectly impacting neural pathways encoding motivation and reward within the brain. Overall, these findings suggest that early life stress events may shape susceptibility traits for compulsive behavior in addiction. In summary, whether it's attachment relationships or stressful events, their influence on individuals during early life is enduring and subtle, and this developmental psychodynamics always impacts inhibitory functions behaviorally. Physiologically, it is invariably associated with the neural foundations that encode motivation and goal-directed or habitual behaviors. From a psychological process perspective, it indeed drives the formation of impulsive behaviors, laying the foundation for the transition of drug use in addiction towards compulsivity.

Neurobiology of the transition to compulsion

Neural basis of cue sensitization

In the preceding sections, we have discussed how personality traits and psychodynamics drive the transition from drug use to compulsive drug use. However, another crucial question is how the brain's relevant neural systems participate in the transition to addiction. First and foremost is the sensitization to cues, where the encoding of cues in a highly motivated state may rely on the phasic release of dopamine in the NAc. The use of fast-scan cyclic voltammetry allows for the measurement of dopamine changes at a sub-second timescale. The results indicate that differences in dopamine responses between reward and prediction occur only in the ST system, with no significant changes observed in the GT system. This suggests that the phasic changes in dopamine in the NAc may not encode the traditional "reward prediction error hypothesis," which relates to the encoding of prediction and actual reward discrepancies. Instead, it may encode the incentive value of cues and is mediated by dopamine in the Nucleus Accumbens core (NAcc). This proposition was further confirmed by systemic administration of flupenthixol, a non-selective dopamine antagonist, which showed that blocking dopamine had an impact on learning in the ST system within the PCA, while the GT system remained largely unaffected. Furthermore, the sustained incentive for cues in the ST system is also associated with the dopamine content in the NAcc. During cue-induced reinstatement tests, the ST system exhibits higher responsiveness compared to the GT system. Blocking dopamine in the NAcc can attenuate this response in the ST system, leading to behavior similar to that of the GT system. The upregulation of the dopamine transporter (DAT) in the ST system may be related to the increased dopamine concentration in the Nucleus Accumbens core (NAcc) induced by drug use. When dopamine is released from neurons into the extracellular space, DAT on the synaptic surface plays a primary role in clearing and recycling excess dopamine. The longer dopamine stays in the extracellular space, the more it interacts with neighboring neurons, leading to dysregulation in the system. Therefore, compared to the GT system, dopamine reuptake in the extracellular space of the NAcc occurs more rapidly in the ST system. However, some addictive substances can increase synaptic dopamine levels by blocking and inhibiting DAT. For example, directly injecting amphetamine into the NAcc can slow down the dopamine reuptake process in the ST system. The synaptic dopamine that is not cleared primarily binds to D1 and D2 receptors and plays a significant role in encoding the incentive salience. Furthermore, in Long-Evans rats, the high expression of DAT phenotype can predict cocaine-like addictive behaviors. Therefore, these results suggest that the transmission of dopamine ability in the NAcc may contribute to the encoding of incentive salience in the ST system and this may also be a susceptibility feature for the transition to compulsive drug use behavior. The formation of the ST is therefore dependent on dopamine, and the pattern of dopamine release in the NACc is crucial for the reward learning process. The dopamine neurons in the NACc primarily originate from dense projections of the midbrain VTA and SNc, and this mesolimbic dopamine neural circuit plays a significant role in encoding cue-induced motivation. It is noteworthy that dopamine neurons output from the VTA and SNc exchange information in the striatum through MSN and glutamatergic neurons from the cortex, forming a circuit with a spirallike structure reminiscent of a serial loop. This also underscores that changes in the neural system sensitized to cue-induced stimulation will further impact the cortical structure and ventral striatum regulation of target behaviors. Another crucial brain region related to cue-induced motivation is the hippocampus. The hippocampus is involved in various types of memory, especially context-related cue cues. Anatomically, the hippocampus can be divided into the ventral hippocampus (VHipp) and the dorsal hippocampus (DHipp). VHipp projects glutamatergic neurons to the NAc and is thus potentially involved in cue-driven motivation through this pathway. For instance, it has been shown that damage to VHipp can impact the concentration of dopamine in the NAc and inhibit cue-seeking behaviors in the ST within the PCA. In summary, the hippocampus, as a regulator of contextual or spatial stimuli, may play a crucial role in the motivational effects of cues on drug seeking. The basolateral amygdala (BLA) also plays a crucial role in cue-induced motivation for drug seeking, and it is the BLA-NAc connectivity loop that is particularly essential. Selective damage to either the BLA or NAc, effectively disconnecting the two, has no impact on self-administration behavior for cocaine but impairs cocaine seeking in secondary reinforcement procedures. This suggests that there are distinctions at the neural circuit level between drug seeking and drug taking. In summary, maintaining cue-controlled drug seeking requires the involvement of the BLA-NAc connection, and this connection forms a serial loop circuit with the involvement of the prefrontal cortex and striatum.

The top-down loss of control and the transition to dorsal striatum control pattern

The projection of dopamine neurons from the midbrain to the striatum mediates the sensitization of cue-induced motivation, and these neural system's plastic changes also lay the foundation for subsequent habitual behavioral patterns. However, the core of transitioning to compulsive seeking in addiction is the inability to break free from habit-dominated behavioral patterns. Therefore, the neural basis of habituation likely represents a core susceptibility mechanism for compulsive seeking. In cue-induced motivation, an individual's behavior is still in a state of balance between goal-directed and habitual actions. As mentioned earlier, within the ST, not only is there sensitization to cues but also changes driven by habitual behaviors. Unlike goal-directed behavior (model-based), this form of habit-driven behavior (model-free) is considered a crucial foundation for the transition to compulsive seeking. This gradual transition to a habitual pattern of behavior, which remains resistant to punishment, may have its neural basis in the difficulty of top-down control from cortical regions to subcortical structures and the dominance of the DLS in behavior control. It is widely recognized that the PFC plays a crucial role in maintaining goal-directed behavior. However, many addictive substances can impair PFC function. For example, in individuals with alcohol addiction, brain regions associated with goal-directed behavior (vmPFC and ventral striatum) have been found to be less active compared to control groups, while regions associated with habit (e.g., the nucleus accumbens shell, equivalent to the dorsolateral striatum in rodents) show increased activity. Although this frontal lobe damage is related to substance intake, individual susceptibility factors may also play a role. Studies involving drug-addicted individuals and their nonaddicted siblings have found that both groups exhibit impairments in frontal lobe function. High impulsivity traits are often associated with difficulties in frontal lobe-mediated behavioral inhibition, suggesting that impulsivity traits in personality may serve as susceptibility factors for addiction. This impairment of PFC function can also affect an individual's executive functions and lead to decision-making deficits, which may, in turn, drive the development of addiction. Impairments in executive functions can result in poor inhibition of habitual behaviors, thereby prioritizing the output of habitual behaviors in response to cues. As the glutamatergic neurons from the prefrontal cortex interact with the dopamine neurons projecting from the VTA and SNc to the striatum in a serial loop circuit, the balance between goal-directed and habitual behavior patterns is likely disrupted, leading to the establishment of habit-dominated behavior patterns (Figure 3). This shift in behavior patterns is thought to be the result of a transition from the ventral striatum to the dorsal striatum. The important roles of the DMS and DLS in compulsive drug use have been confirmed in both human and animal research. For example, the anterior part of the DLS (aDLS) plays a prominent role in the transition to compulsive seeking; functional magnetic resonance imaging (fMRI) studies in humans have shown increased activation in the DMS when individuals who engage in recreational drug use see drug-related cues, while addicted individuals show enhanced DLS activity. The "seekingtaking" chained procedure distinguishes compulsive seeking and taking of drugs. In this paradigm, animals must perform an action (such as pressing a lever) to "seek" another task that allows them to "take" the drug. After several weeks of training, a shift in control from the DMS to the DLS was observed in animals that were insensitive to reinforcement devaluation. This indicates a shift from goal-directed to habit-dominated behavior patterns in this paradigm. Furthermore, in the same training procedure, when rats exhibited habit-dominated behavior, inhibiting DLS activity forced the habit system offline, and rats again exhibited sensitivity to reinforcement devaluation. In summary, these results suggest that in the transition to compulsive seeking, seeking behavior dependent on the DMS gradually becomes dominated by habitual seeking responses dependent on DLS activity.

Therefore, as it stands, the significant individual differences observed in addiction are not only related to sensitization to cues during drug use but, more importantly, to an overreliance on the DLS during the drug use process and an inability to break free from habit-dominated behavior driven by the DLS. When faced with punishment, individuals who cannot disengage from the DLS will exhibit characteristics of compulsive drug use (Figure 4). The dopaminergic neurons projecting from the VTA to the NACc are associated with GABAergic MSN in the NAC region. GABAergic MSN neurons project back to subcortical areas, inhibiting dopamine neurons located outside the VTA. These dopamine neurons subsequently project to the NAC shell. This circuit forms a feedback mechanism, and after several iterations, it reaches the SNc, which sends dopamine neuron outputs to the DLS. PFC regulates this serial loop circuit by sending powerful glutamatergic neurons to both the NAc and DLS. Indeed, during the transition to compulsive drug use, the PFC gradually loses control over this serial loop circuit. In the competition between goal-directed and habit-directed behaviors, control is gradually shifted to the habit system dominated by the DLS. This shift in control dynamics is a crucial aspect of the development of compulsive drug-seeking behavior.

Conclusion

The differentiation between ST and GT phenotypes in the PCA may indeed reveal susceptibility traits present in addiction. In ST individuals, several traits have been identified that may be related to compulsive drug-seeking behavior in addiction, such as poor top-down behavioral control, attentional deficits, and impulsive behaviors. These traits are not limited to animal models; similar or analogous traits have been found in human studies, suggesting the potential for translating individual differences identified in animal models to human research. Therefore, we summarized the role of personality traits, specifically novelty seeking and impulsivity, in addiction. Overall, individuals with these two traits exhibit core features of the ST phenotype: poor attention and difficulties in behavioral inhibition. Furthermore, we found that ST behavior may be related to early-life environmental events and experiences, such as early stress and attachment relationships. This may shed light on the psychodynamics leading to compulsive drug use in humans. Finally, we summarized the current understanding of the neurobiological mechanisms underlying compulsive drug use. These studies suggest that the transition from controlled drug use to uncontrolled, compulsive drug-seeking behavior is rooted in habitual behavior. These susceptibility traits for addiction are likely influenced by genetics and experiences. Therefore, future research in this field may employ genetic studies, longitudinal tracking studies, and crossaddiction spectrum studies to measure the predictive utility of these susceptibility traits in addiction and to separate the pharmacological effects of addictive substances.

Acknowledgments

Funding: In conducting this research, no external funding or grants were received.

Declaration of Interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

The authors declare no competing financial interests.

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