Regulation of addiction by the insular cortex: The interplay between interoception and cognitive function

Summary

The insular cortex (IC) functions as a pivotal core for interoception. Functional magnetic resonance imaging reveals how the IC integrates internal and external stimuli by observing its neural activation patterns. It facilitates interactions among sensory, emotional, and cognitive inputs via specific neural circuits. The finding that IC injury can reduce nicotine intake and the pioneering research on the involvement of the IC in addiction. Subsequently, human studies discovered that the IC amplifies drug-derived pleasure, strengthening the link between cravings and drug use, thus increasing compulsive drug-seeking behavior. During withdrawal, the IC processes negative emotions, prompting animals to increase drug intake to alleviate distress and other withdrawal symptoms, thus promoting continued drug abuse and relapse via negative reinforcement. Moreover, it participates in the consolidation/reconsolidation of drug memories, which may be linked to synaptic plasticity. The dysfunction of the IC leads to cognitive deficits, which influence decision-making and motivation and indirectly regulate drug-driven behaviors. Despite growing interest in the role of the IC in addiction, the precise mechanisms are still not fully understood. This article reviews the IC’s role in addiction, highlighting its direct impact on behaviors like craving and drug-seeking via interoception and its influence on addiction memory. It also examines the IC’s indirect effects on decision-making and motivation through cognitive functions in risk assessment and maintaining motivation. To advance addiction neurobiology research, future studies must explore the interaction between environmental factors and neural mechanisms in driving addiction. Including observable behaviors in research will facilitate the translation of findings into effective substance use disorder treatments.

Graphical abstract

Biological sciences; Natural sciences; Neuroscience

Introduction

The insular cortex (IC) is a structurally complex and highly interconnected region, serving as a key cortical center. It plays a critical role in interoception, sensory processing, autonomic regulation, self-awareness, and social conduct.^1,2 The IC is divided into three central regions: the anterior (aIC), middle (mIC), and posterior insular cortices (pIC). Cytoarchitecturally, the IC is organized from dorsal to ventral, known as the granular, dysgranular, and agranular subregions, which are primarily composed of excitatory glutamatergic neurons and inhibitory γ-gamma-aminobutyric acid (GABA) interneurons.^1,3

As a dynamic interface, the IC integrates diverse inputs into subjective experiences and decision-making based on the physical and emotional state, playing a critical role in interoception.² For instance, a functional magnetic resonance imaging (fMRI) study found that during the Iowa gambling task (IGT) which assesses decision-making ability, the dorsal aIC shows stronger functional connections with the prefrontal region involved in executive control.⁴ This enables individuals to make informed decisions based on consequences when facing high-risk choices. The ventral aIC is primarily connected to the amygdala-striatal circuitry involved in linked to emotions, motivation, and reward. Participants who underwent event-related fMRI while performing the monetary incentive delay task showed elevated activity of the ventral aIC and the amygdala during reward anticipation, which in turn activated the cortico-striatal networks taking part in motivation and reward-seeking behavior.⁵ Lastly, the pIC primarily receives and integrates interoceptive signals related to somatosensory and motor functions.^4,6 This multimodal sensory information is then processed in the mIC and subsequently transmitted to the aIC, which further processes the information and interacts with regions involved in cognitive and emotional control.⁷ These sensory inputs influence an individual’s motivation, serving as a driving force for drug-seeking behavior. In the animal gold-standard model of addiction-intravenous drug self-administration (SA), drug seeking is measured by recording the number of lever presses made by animals.⁸ Inactivation of the aIC by muscimol and baclofen increases cue-induced reinstatement of heroin seeking in rats, whereas inactivation of the pIC prevents cue-induced reinstatement.⁹ These findings suggest that the aIC and pIC have opposing roles-inhibiting or promoting cue-driven behaviors.

The IC has extensive connections with emotion-related brain regions, such as the thalamus and prefrontal cortex (PFC), making it possible to integrate emotional signals and regulate responses.¹⁰ The emotions of mice can be reflected through various behavioral and physiological indicators. For example, when mice are in a state of anxiety or fear, their exploratory behavior is inhibited during open field tests (OFT) and in the elevated plus maze (EPM). Emotions play a positive and negative reinforcement in the formation of substance use disorders (SUD). Specifically, when mice take drugs, such as cocaine, the drugs prompt the brain to release large amounts of dopamine, resulting in positive emotional experiences, such as pleasure and excitement.¹¹ This positive emotion reinforces the drug-taking behaviors. In the SA model, mice will repeatedly press a lever to obtain cocaine, and the lever pressing is reinforced by the rewarding effect of cocaine. Addictive drug use elicits positive emotional experiences, while withdrawal induces negative ones. Research has shown that both granular and agranular cortices are involved in the acquisition of conditioned place aversion (CPA) triggered by acute morphine withdrawal.¹² In addition, neurons within the IC encode emotions, including pleasure, aversion, fear, and pain, which contribute to the formation and consolidation of emotional memories.¹³ These memories significantly contribute to the initiation of subsequent addictive behaviors through mechanisms, such as strengthening associations, consolidating memories, triggering relapse, and modulating susceptibility.¹⁴

The IC is involved in reward anticipation, decision-making, and motivation maintenance, all of which are closely related to addictive behaviors. Studies have shown that deep-layer IC neurons (especially those expressing the Fezf2 gene) regulate motivated behavior via a neural circuit projecting to the nucleus tractus solitarius (NTS) in the brainstem. When mice are water-restricted, activation of the IC-NTS circuit significantly enhances their motivation to consume water.¹⁵ Additionally, the IC also facilitates self-regulation, which refers to an individual’s ability to monitor, evaluate, and adjust their behaviors, emotions, cognitions, and physiological states. The IC integrates cognitive, emotional, and interoceptive information, thereby facilitating decision-making.¹⁶ By enhancing self-regulation ability, individuals can better cope with cravings, thereby reducing the risk of relapse and drug use.¹⁷ As such, through its involvement in interoception, emotions, memory, and cognition, the IC plays a central role in regulating addictive behaviors.

Evidence from rodent behavioral studies indicates that the aIC activity is essential for behaviors associated with cocaine, heroin, and nicotine.^18,19 For example, the activation of calmodulin-dependent protein kinase II-positive neurons in the aIC is involved in the formation of conditioned place preference (CPP) for drug-related environments.²⁰ In contrast, activation of GABAergic neurons following memory retrieval impairs morphine memory reconsolidation.²¹ These studies suggest that both glutamatergic and GABAergic neurons of the IC play critical but different roles in drug behaviors. In addition, the IC receives input from limbic structures, including the amygdala (central amygdaloid nucleus, CeA, and basolateral amygdala, BLA), nucleus accumbens (NAc), and ventral tegmental area (VTA).^22,23 Glutamatergic inputs from the aIC to the BLA enhance rewarding behavior during a real-time place preference task (rtCPP).²³ Conversely, inhibition of glutamatergic projections from the BLA to the aIC accelerates rtCPP extinction, as evidenced by a gradual reduction in time spent by the animal in the drug-paired environment.²⁴

Clinical studies have demonstrated altered connectivity between the IC with the dorsolateral PFC, the ventromedial PFC, and the anterior dorsal cingulate cortex in patients who have quit smoking.²⁵ This change in connectivity has been observed in individuals who have successfully quit smoking, suggesting a potential involvement of the IC in smoking. Indeed, smokers with IC damage are more likely to quit smoking and maintain abstinence, and they are very unlikely to consciously smoke afterward.²⁶ Moreover, altered functional connectivity of the IC has been observed in cocaine-dependent patients²⁷ and during opioid withdrawal,²⁸ providing additional evidence for a correlation between drug cravings and alterations in the neural circuits of the IC.

Thus, the IC is closely related to addictive behaviors. It not only directly regulates addictive behavior and addiction-related memories, contributing to the development of drug abuse and relapse, but also facilitates decision-making that favors drug reuse and drug use motivation through the integration of cognitive and motivational inputs.^16,29 Despite growing interest, the specific characteristics and IC mechanisms related to addiction are not well defined. In this review, we examine the existing literature from basic and clinical research, as well as structural and functional neuroimaging studies, to delineate the critical role of the IC in SUD and elucidate the mechanisms through which it exerts its influence. We aim to provide a novel perspective on the IC and clarify its specific role in addictive behaviors.

The insular cortex and addiction behavior

First, the IC via interoception enhances the stimulation effects of drugs. Long-term repeated drug use creates a mismatch between an individual’s perceived sensations and actual physiological states,³⁰ which intensifies drug cravings and use. This further led to compulsive drug-seeking behavior. For example, in rodents, chemogenetic inhibition of the aIC-orbitofrontal cortex (OFC) circuit reduces compulsive drug-seeking, while its activation induces it.³¹ Additionally, interoception is involved in learning to interpret positive and negative emotions, including reward and aversion. Collectively, the relationship between interoception and addictive behavior is multifaceted, involving both physiological states and the perception and regulation of emotions. The following sections detail the specific effects of interoception in SUD.

The interoception center-insular cortex regulates addictive behavior

Interoception denotes the awareness of the body’s internal states. Neurotransmitters in the thalamus transmit visceral sensations to the IC of rats, primarily through non-N-methyl-D-aspartate (NMDA) receptors, muscarinic acetylcholine receptors (mAChR), and the GABAergic system.^32,33 Clinical studies have found that the interoceptive stimulus of alcohol consumption, such as the feeling of being “excited” or “relaxed”, can be measured through subjective reports (e.g., visual analog scale) and physiological indicators (e.g., heart rate variability).³⁴ Such measures can coincide with reinforcing events, forming associations that lead to continued alcohol or drug use and relapse. This suggests that interoceptive stimuli for drugs serve as cues that impact emotions and guide reward-seeking behaviors. Conversely, long-term drug use affects interoceptive processing.³⁵ In clinical studies, alcohol users expect to achieve certain interoceptive states (such as relaxation or excitement) when drinking. A mismatch between expectations and the actual perception of interoceptive state may contribute to a compensatory increase to achieve the desired state.³⁰ Individuals with stimulant use disorders (cocaine and amphetamine) exhibit exaggerated perception of heartbeat sensations, which is associated with reduced activation in the granular subregions. On the other hand, repeated stimulant use inhibits the IC’s ability to perceive changes in heartbeat and continues drug use.³⁶ The IC plays a pivotal role in addictive behaviors by establishing new homeostatic points within the dysregulated system.³⁷

Craving is an intense desire for a substance. In animals, it is often manifested as lever pressing (drug seeking) or an approach to the water source (food trough). Water-restricted mice will readily approach the water trough and make more licks than non-restricted animals.³⁸ Fiber photometry recordings indicate that water-restricted mice show elevated neurotransmission in the IC while drinking water. Correspondingly, chemogenetic activation of the pIC neurons projecting to the BLA decreases water consumption in mice.³⁹ These findings suggest that the pIC-BLA pathway contributes to the control of the thirst responses (aka reward seeking/craving). The stimulation of mAChR in the IC is associated with drug cravings when drug-related memories are retrieved in mice undergoing CPP.⁴⁰ In addition, studies have shown that the IC is activated during drug cravings in users of cigarettes, cocaine, alcohol, and cannabis.^26,41,42 The fMRI study that assessed alcohol craving levels in 91 patients with alcohol use disorder (AUD) found a significant correlation between IC activation and alcohol craving.⁴² In addition, smokers with IC injury report reduced cravings and increased desire to quit smoking, suggesting that the IC may be a critical brain region mediating nicotine craving.²⁶ Interestingly, the gambling craving paradigm in pathological gambling patients often does not show IC activity.⁴³ These studies indicate that the activation of the reward system by the aIC might be important for drug-taking and seeking. Indeed, drug cravings-induced habitual use may further result in the formation of compulsive drug-seeking behavior.

Compulsive drug-seeking refers to the behavior in which individuals persistently seek drugs despite negative consequences and is one of the clinical symptoms of drug addiction. The transition from craving to compulsive drug-seeking behavior is shaped by reinforcing contingencies and learning.⁴⁴ When individuals experience the pleasurable effects of drugs, these sensations reinforce drug taking, making it more likely for users to repeat such behaviors in the future. As the frequency of drug use increases, individuals gradually develop conditioned responses to drug-related cues, even compulsive drug-seeking behavior.⁴⁵ The clinical findings indicate that in AUD, long-term alcohol consumption leads to an increase in perineuronal nets (PNs) surrounding neurons in the IC.⁴⁶ PNs influence neuronal firing and plasticity, thereby contributing to the development of compulsive drinking.⁴⁷ Animal research has shown that inhibition of the aIC reduces relapse of nicotine-seeking triggered by environmental or cue stimuli,^19,48 and attenuates drug-environment-induced relapse of cocaine-seeking behavior.¹⁸ Inhibition of the OFC-aIC pathway effectively reduces the rats’ compulsive drug-seeking behavior, while activation of this pathway promotes compulsive drug-seeking behaviors.³¹

Withdrawal-induced negative emotions (including anxiety and depression) are widely recognized as significant factors that trigger and exacerbate relapse. Specifically, interoception can enhance attention to bodily signals related to negative emotions, thereby affecting emotion regulation strategies.² For example, during drug or alcohol withdrawal, interoception in the IC may prompt individuals to seek drugs to alleviate the discomfort of withdrawal symptoms.¹² Clinical studies found a significant correlation between heightened interoception sensitivity and anxiety levels; this increased sensitivity interacts with abnormal activation of the amygdala.^49,50 Animal studies have identified the IC’s involvement in anxiety-like behavior during morphine withdrawal in mice. Specifically, mice undergoing 28 days of morphine withdrawal show a significant decrease in the time spent in the central area of the OFT, indicative of increased anxiety-like behaviors.⁵¹ The IC’s ability to encode emotional changes resulting from drug consumption and withdrawal further supports this perspective.¹⁶ Additionally, the IC is closely linked to depression. A structural MRI study found decreased gray matter volumes in the right pIC and left ventral aIC, as well as increased gray matter volumes in the left dorsal aIC in patients with bipolar disorder.⁵² Meanwhile, disruptions in the IC in patients with depression might be linked to an increased perception of interoceptive awareness and a negative bias in emotional processing.⁵³ However, the mechanism by which the IC is involved in withdrawal-induced negative emotions remains unclear.

The IC functions as an interoceptive center, amplifying the euphoria and pleasure derived from drugs. Prolonged drug exposure, in turn, impairs interoceptive processing, thereby inducing drug cravings and relapses. These cravings and habitual drug use contribute to compulsive drug-seeking behavior, which further perpetuates drug use and the risk of relapse. Moreover, emotions associated with interoception that are mediated by the IC may constitute one of the mechanisms through which the IC modulates addictive behaviors. The IC is implicated in addiction regulation via its role in interoception and its connections to various brain regions. Nonetheless, numerous enigmas remain regarding the IC’s mechanisms of addiction regulation. Investigating the addiction mechanisms related to the IC can enhance our understanding of how addiction develops (Figure 1).

Figure 1.

Projection of the insular cortex and related molecule

A simplified scheme of the insular cortex projection and related molecule visualized on the rodent brain. The insular connections with sensory, emotional, motivational, and cognitive systems. Neurons or molecules in black font indicate that research has proven their involvement in addiction, while those in blue font suggest a potential role.

NAc, nucleus accumbens; BNST, bed nucleus of the stria terminalis; OFC, orbitofrontal cortex; PFC, prefrontal cortex; VTA, ventral tegmental area; AMY, amygdala. D1 D2-MSNs, D1 MSNs (D1-type medium spiny neurons), D2 MSNs (D2-type medium spiny neurons); CRF neurons, corticotropin-releasing factor neurons; ERK neuron, phosphorylated extracellular signal-regulated kinase neuron; GABAergic, γ-aminobutyric acid neurons; DAergic, dopamine neuron; Gluergic, glutamatergic neurons; CaMKII neuron, calcium/calmodulin-dependent protein kinase II neurons; PV neuron, parvalbumin neuron. mAChR, muscarinic acetylcholine receptor; Hcrt-1R: hypocretin receptor 1; CB1R, cannabinoid receptor type 1; non-NMDAR, non-N-methyl-D-aspartate receptor; D1R, dopamine D1 receptor; NMDAR, N-methyl-D-aspartic acid receptor; AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor; DA, dopamine; Glu, glutamatergic; GABA: γ-aminobutyric acid; SYT2: synaptotagmin 2; RIM3: regulating synaptic membrane exocytosis 3; Wnt, wingless-type MMTV integration site family; BDNF, brain-derived neurotrophic factor; NT-3: neurotrophin-3; and ERK, extracellular signal-regulated kinase.

The potential mechanisms of insular cortex regulation of addictive behavior

Hypocretin (Hcrt) is a neuropeptide synthesized by neurons located in the lateral hypothalamus and signals through two receptors: Hcrt-1 receptors and Hcrt-2 receptors.⁵⁴ The pharmacological blockade of Hcrt-1R in the IC reduces nicotine consumption in rodents in a nicotine SA paradigm.⁵⁵ The expression of dopamine D1 receptors (D1) and dopamine D2 receptors (D2) in the IC might be relevant to SUD.⁵⁶ Activation of aIC D1 receptors enhances the activity of dopaminergic neurons, thereby further modulating the rewarding effects of nicotine and nicotine-motivated behaviors.⁵⁷ Blockade of aIC D1 receptors reduces cocaine intake in rats,⁵⁸ as evidenced by a significant reduction in lever-pressing responses for cocaine in the SA paradigm. Thus, D1 receptors, rather than D2 receptors, in the aIC appear to be involved in the SUD. It should be noted that the density and distribution of Hcrt and dopamine (DA) receptors in the IC may vary across species, which could influence the translational relevance of these findings to human addiction.

In addition to neurotransmitter delivery, receptors, and ion channels in the IC participate in the regulation of addiction-related behaviors. For instance, inhibition of Wnt production in NAc in rats has been shown to block amphetamine-induced CPP acquisition and expression.⁵⁹ Activation of the Wnt signaling pathway in the IC after long-term morphine withdrawal induces anxiety-like behavior in mice, indicated as the increased time spent in the closed arms of the EPM. This increase in anxiety-like behavior is associated with an increased risk of drug-seeking behavior.⁶⁰ In addition, NMDA receptor signaling may become sensitized during withdrawal to regulate drug seeking.⁶¹ This sensitization was observed through the increased NMDA receptor-mediated synaptic currents in brain slices from animals undergoing withdrawal. Acute withdrawal is also associated with decreased mRNA expression of the big conductance calcium-activated potassium channel (BK channels) in multiple cell populations of the IC.⁶² The decrease in BK channel expression is correlated with increased anxiety-like behavior and drug-seeking behavior in withdrawal models, indicating that the BK channel plays a role in regulating these behaviors. The BK channel mechanism holds promising targets for treating negative emotions and reducing the risk of relapse in patients with AUD. These research advances provide insights into different aspects of the molecular mechanisms of IC in addiction and offer new avenues for future research that would help us to understand the molecular mechanisms of IC underlying addiction.

Circuit-based studies have reported that inhibition of glutamatergic projections from the aIC to the CeA or NAc reduces the recurrence of methamphetamine or alcohol use in rodents, respectively^63,64 (Figure 1). The glutamatergic neurons in the IC-ventral bed nucleus of the stria terminalis (BNST) control reward-related behavior, activation of this pathway promotes the expression of CPP in mice.⁶⁰ In addition, activation of cannabinoid receptor type 1 inhibits the activation of IC-BNST corticotropin-releasing factor (CRF) neurons.⁶⁵ CRF neurons are associated with stress responses and negative emotions. When these neurons are inhibited, it may alleviate these negative emotions, which in turn indirectly affect an individual’s perception of and pursuit of rewards.¹⁷ Studies have found that there was abnormal activation of the aIC and the OFC->aIC neural circuits in rats exhibiting compulsive drug-seeking behavior.³¹ Another study found that increased obsessive-compulsive behavior is associated with low excitability of layer 5 pyramidal neurons in the adolescent rat aIC and decreased glutamatergic synaptic input to the IC.⁶⁶ This indicates that modulating the excitability of IC neurons may potentially serve as a therapeutic approach for compulsive drug-seeking behavior. These studies elucidate the role of the IC in addictive behaviors and commence delineating the neural pathways that link the IC to brain regions implicated in reward and emotion, highlighting how these connections influence addictive behavior. Future research should bridge the translational gap between rodent models and human clinical outcomes to develop new SUD treatments.

Positive and negative reinforcement work together to promote the development of SUD. Positive reinforcement in drug use refers to the increased likelihood of drug-use behavior due to the direct rewarding consequences of drug-induced euphoria. Here, the reinforcer is the euphoria induced by the drug itself that reinforces drug-use.⁶⁷ The IC promotes SUD through positive reinforcement in the following main ways: (1) IC participation in the rewarding effect. Specifically, the activation of aIC-NTS neural pathways leads to an increase in DA levels in the striatum during reward learn, thereby reinforcing reward behavior.¹⁵ (2) Physiological dependence and tolerance. Long-term use of addictive drugs can lead to adaptive changes in the body, resulting in physiological dependence and tolerance, which further reinforce addictive behaviors.⁶⁸ The IC solidifies the connection between substance use and intrinsic motivation, facilitating relapse and the development of cravings. This precipitates compulsive drug-seeking behaviors, ultimately culminating in chronic drug dependence.⁶⁹ (3) Positive mood. The aIC plays a key role in emotional experience, integrating bodily sensations with emotional experiences to enable individuals to better understand and regulate emotions.² In drug use, the ventral IC may contribute to positive emotions associated with drug-use, thereby reinforcing drug-taking and seeking.⁷⁰

Furthermore, the negative reinforcement effects of the IC are predominantly observed during the withdrawal phase of SUDs. Negative reinforcement is associated with the reduction of aversive states (such as anxiety and irritability) in drug use. These aversive states serve as negative reinforcers, increasing the likelihood of drug-seeking behavior to alleviate these unpleasant feelings.⁷¹ In addiction research, the IC is involved in processing signals related to the interoceptive effects of drug-use and internal states during withdrawal. Specifically, the IC may respond to and process interoceptive cues associated with withdrawal.⁹ A mouse model study of alcohol consumption found that when certain negative emotional states and physiological changes occur in the absence of alcohol, the chemogenetic activation of the endocannabinoid system in the IC-BNST pathway helps to regulate these states and responses, making behaviors related to alcohol seeking and consumption more likely to occur.⁶⁵ In addition to negative emotions, the aIC exerts a more important influence on the regulation of withdrawal-related negative internal feelings on drug-seeking behavior in rats. Inactivation of the pIC impairs the acquisition of morphine-induced CPP, while inactivation of the aIC attenuates the acquisition of naloxone-precipitated CPA.¹² These results indicate that the aIC and pIC have distinct functions in regulating drug addiction and withdrawal-related behaviors. The negative reinforcement effect of the IC in addiction is primarily caused by negative emotional experiences and interoceptive regulation during withdrawal, providing new targets and directions for the treatment of SUD.

In conclusion, the IC is involved in addictive behaviors through its participation in the reward effects, physiological dependence, and both positive and negative reinforcement. The role of IC in encoding and storage of emotional memory is emphasized, and addiction is considered a pathological memory. This suggests that further exploration of the IC’s contribution to addictive memory is warranted. The IC is involved in reward memory and learning the association between drugs and context to regulate contextual reward memory.¹⁸ Studying addiction memory reveals the neurobiological mechanisms of drug addiction, which consequently can help us understand the changes in brain structure and function following drug use.

The insular cortex and addiction memory

Addiction involves learning and memory processes, which are essential for the development and maintenance of SUD.⁷² Addiction memory is formed by the repeated association of the addictive substance with relevant cues or environments, which serves as one of the foundations for the long-term persistence of addictive behavior.⁷³ Therefore, investigating the underlying mechanisms of the encoding, storage, and retrieval of addictive memories is essential for the development of effective intervention strategies. The IC is involved in memory formation, integration, and regulation, particularly in processing emotional and interoceptive information. These functions help us understand the role of the IC in addiction memory.

The insular cortex participates in drug memory

Animal studies have consistently implicated the IC in taste and taste memory recognition.⁷⁴ For example, when an animal learns that a novel taste (conditioned stimulus; CS) is linked to an aversive sensation (unconditioned stimulus; US), it rejects the taste in subsequent encounters, developing a persistent taste aversion known as conditioned taste aversion (CTA).⁷⁵ This learning process creates a connection between gustatory stimuli and negative outcomes, similar to how reward memory links stimuli with positive and beneficial consequences.⁷⁶ Addictive drugs, such as cocaine or morphine can induce both CPP and CTA, indicating that these drugs can elicit both positive rewards and negative aversions.⁷⁷ CTA and reward memory may share certain pathways in their memory neural mechanisms.

Similar to CTA, contextual memories of drugs associate a particular location with the rewarding or aversive consequence of a drug. Environmental cues associated with drugs act as CS, which can induce drug-seeking behaviors in individuals with SUD.³⁵ In rats, pharmacological inactivation of the aIC by muscimol and baclofen reduces the reinstatement of cocaine-seeking behaviors triggered by the CS-drug environment.⁷⁸ Contreras et al. demonstrated that the aIC is involved in the association of contextual cues and drug effects, supporting the IC’s role in drug-related memory function.⁷⁹ Moreover, exposure to drug-related cues can also trigger reactivation of drug memory and drug-seeking behavior. There is evidence that the connection between the IC and the NAc may mediate the retrieval of reward memory. The NAc core and IC were shown to be activated following cue-induced morphine-seeking behavior, and glutamatergic IC-NAc core input was necessary for the resumption of cue-related drug-seeking.⁸⁰ In addition, neural ensembles in the IC can store memories related to both rewarding and aversive emotions, and regulate the retrieval of these memories through specific projections to the NAc.⁸¹ The activation of this neural circuit is closely associated with the retrieval of reward-related memories.

In addition to its involvement in forming memories, the IC seems to be implicated in both the consolidation and reconsolidation processes of memory. For instance, in rats, neurotrophin-3 (NT-3), which binds to tropomyosin receptor kinase C receptors highly expressed in IC, can strengthen the memory trace of CTA induced by lithium chloride, thereby demonstrating a significant role of NT-3 in the consolidation of aversive memories in the neocortex.⁸² The CTA memories are associated with increased brain-derived neurotrophic factor (BDNF) expression in the IC during reconsolidation.⁸³ Thus, BDNF synthesis and signaling in the IC have been identified as key players in memory reconsolidation. Altogether, the IC is in the consolidation and reconsolidation of taste aversion memories and reward memories, regulating memory formation and retention.

Interventions targeting reconsolidation have been shown to diminish drug-reward memory in rodents, but this is not always true. For example, inactivation of the aIC after cocaine context memory retrieval fails to disrupt subsequent drug seeking. However, microinjections of baclofen into the aIC right after retrieval inhibit morphine-induced CPP.⁸⁴ This is most likely due to the disruption of the reconsolidation of morphine memory. Specifically, the activation of GABAergic neurons eliminates the established morphine-CPP and prevents the risk of relapse, most likely due to disruption of morphine memory reconsolidation. Taken together, these findings highlight the important role of the IC in the reconsolidation of drug-related memory.

The potential mechanisms of insular cortex involvement in memory

A variety of neurotransmitter systems and neurotrophic factors in the brain participate in memory formation. Synaptic tag protein 2 and regulating synaptic membrane exocytosis 3 play crucial roles in the addiction process by regulating glutamatergic synaptic transmission, participating in the formation and consolidation of addiction memory, responding to addiction-related cues, and promoting the expression of addictive behaviors.⁸⁵ In the IC, these proteins may also be involved in regulating the formation and consolidation of addiction-related memories. NT-3, like BDNF, is an important neurotrophic factor involved in neuronal survival and function. BDNF is involved in memory processes by regulating neuronal activity and inhibiting apoptosis, while NT-3 affects memory consolidation by enhancing memory traces.^82,83,86 The importance of BDNF and NT-3 in addiction has been partially revealed, but many specific mechanisms underlying drug memory in the IC remain unclear. In general, CTA memory may share these molecular mechanisms with reward memory formation.

The connections and projections of the IC with limbic structures such as the VTA and the BLA are critical for memory (Figure 1). First, the VTA is the primary source of dopamine in the brain and is regulated by aIC glutamatergic neurons, which in turn regulate the acquisition of drug-related affective states and drug-rewarding contextual memory.⁸⁷ DAergic and GABAergic neurons in the VTA contribute to the formation and maintenance of reward-contextual memories by regulating dopamine release through projections to the IC.⁸⁸ Animal studies demonstrated that retrieval of CTA memory increases synaptic inhibition of the projection neurons from the IC to the BLA, specifically manifested by an increase in the frequency and amplitude of parvalbumin (PV)-dependent inhibitory postsynaptic currents.⁸⁹ This inhibitory effect is mediated by the activity of PV interneurons in the IC, highlighting the critical role of PV interneurons in the retrieval of aversive memories. Given the similarities in the neural mechanisms underlying reward and aversive memories, as well as the observation that ventral pallidum neurons (which have similar functions to PV) respond to reward-related cues by specifically encoding the incentive value of these cues, we can reasonably speculate that PV is involved in the retrieval of reward memories.⁹⁰

The glutamatergic projection from the BLA-aIC is critical for maintaining rewarding contextual memory, as its photoinhibition accelerates extinction and impairs the reinstatement of rtCPP in mice.²⁴ Specifically, this glutamatergic projection can activate both excitatory pyramidal cells and inhibitory GABA neurons in the aIC, forming a typical feedforward inhibition effect. This inhibitory effect is critical for the regulation of memory retrieval and reward-related behaviors.⁹¹ Moreover, the number of phospho-extracellular signal-regulated kinase (ERK)-positive neurons in the mPFC significantly increases when mice encounter palatable food, activating the projection from the mPFC-aIC to form safe taste memory traces.⁹² Inhibition of this pathway decreases the proportion, memory specificity, and behavioral performance, while optogenetic activation enhances these responses.⁹³ Drug cues regulate the retrieval and regression of drug memories via glutamate receptor transport in the mPFC.⁹⁴ The synergistic effects derived from activation of these proteins are critical for emotional and reward processing, providing an important neurobiological basis for understanding addictive behavior.

Alterations in gene expression in IC neurons are also implicated in learning and memory. For example, rats subjected to CTA conditioning received intra—IC microinjections of 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole to inhibit median raphe nucleus synthesis or MS-275 to suppress deacetylation of histones. Transcription inhibition immediately and 7 h after CTA acquisition impaired the CTA memory consolidation, whereas inhibition of histone deacetylation strengthened this memory.⁹⁵ These findings suggest that CTA memory requires transcriptional regulation in the IC for memory consolidation. Drug abuse induces changes in gene expression in the brain, and exposure to psychoactive substances can stably upregulate or downregulate the mRNA levels of certain individual genes.⁹⁶ There is evidence that long-term chronic drug treatment can activate the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP response element-binding protein (CREB) signaling pathway, which in turn affects the expression of ΔFosB.^97,98 The injection of baclofen, a GABA agonist, into the IC disrupts both the reconsolidation and consolidation of morphine CPP memory; in both cases, the erasure of morphine CPP memory is associated with a long-term decrease in morphine-related ΔFosB expression.⁸⁴ Studies on memory reconsolidation have shown that inhibition of DNA methylation in the aIC disrupts the reconsolidation of morphine withdrawal memory, indicating that DNA methylation plays a regulatory role in the IC in the memory reconsolidation process.⁹⁹

The mechanisms of addiction-related memories involve multiple levels, including neurotransmitter systems, signal transduction pathways, neuronal circuits, and gene expression regulation, which ultimately lead to changes in synaptic plasticity. Long-term depression (LTD) and long-term potentiation (LTP) are major forms of synaptic plasticity. The activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor in the IC is required for the expression of CTA,¹⁰⁰ which subsequently induces LTD in the IC by promoting AMPA endocytosis. The BLA->IC circuit is associated with changes in synaptic plasticity related to memory consolidation and extinction. High-frequency stimulation of the BLA can induce LTP in the IC, leading to more persistent aversive memory regression.²⁴ Nicotine may facilitate LTD in layer V pyramidal neurons through the enhancement of GABAergic neurons in the IC.¹⁰¹ In addition, cocaine-induced ERK activation leads to long-term stable alterations in synaptic plasticity and rapidly induces changes in synaptic transmission events, thereby controlling cocaine-seeking behavior.¹⁰² However, it is unclear whether other drugs of abuse activate the ERK signaling pathway in the IC and induce changes in synaptic plasticity.

The IC is a complex brain region that significantly contributes to memory formation and processing. CTA memory is similar to reward memory and may share certain pathways in terms of mechanisms. The IC regulates reward memory through the association between the drug and its environment, and further participates in the regulation of memory consolidation and reconsolidation. Addictive drugs activate intracellular signal transduction pathways by altering neurotransmitter release, which in turn modifies neurotrophic and transcription factors. These changes eventually cause alterations in synaptic plasticity and the long-term persistence of addiction memories. The interplay of these mechanisms forms a complex network underlying drug memories and drug-motivated behaviors.

Insular cortex regulation of addictive behaviors through cognition

Patients with SUD exhibit significant deficits in multiple cognitive domains that can persist and impact both withdrawal and treatment efficacy. The complex connections between the IC and other brain regions underscore its critical role in cognition. Addicted individuals often display impulsive and short-sighted behavior, which makes it difficult for them to evaluate long-term and short-term consequences. Several clinical studies reported that injury or dysfunction to the IC leads to these cognitive deficits, affecting an individual’s decision-making ability and motivational control.²⁹

Integration of information by the IC to guide decision-making

“Risk assessment” refers to the cognitive evaluation process of the potential negative consequences associated with a specific action, while “risk decision-making” involves choosing to take a certain action despite negative consequences. A defining feature of addiction is aberrant risk assessment and decision-making in addicts. Chronic drug use impairs the capability for risk assessment and making reasonable decisions. Clinical evidence indicates that methamphetamine-dependent individuals are more likely to continue choosing risky options after experiencing losses, indicating impaired processing of risks and persistent risk-taking behavior.¹⁰³ This impaired risk processing ability may account for their continued drug use.¹⁰⁴

In the gambling tasks, this is a commonly used experimental paradigm in the study of risk decision-making, where participants are required to select cards from decks that offer varying levels of rewards and punishments. The specific behavior measured in the IGT is the tendency to choose decks that provide high immediate rewards but also bring high long-term losses (high-risk and high-reward decks) over those that offer lower immediate rewards but fewer long-term losses (low-risk and low-reward decks).²⁹ Similarly, methamphetamine-treated rats are more likely to choose the high-risk, high-reward options, which is consistent with the results of clinical studies. Immunohistochemical analysis showed that the high-risk behaviors in rats are associated with abnormal cFos activation in the IC.¹⁰⁵ In contrast, inactivation of the aIC shifts the rats’ preference toward options with higher reward frequency and lower punishment and reduces risk pref.¹⁰⁶ The aIC lesions have a bidirectional impact on risky decision-making in gambling tasks, specifically contingent upon whether rats exhibit risk-seeking or risk-averse behaviors.¹⁰⁷ Clinical studies have shown that individuals with SUDs exhibit increased activation in the IC during tasks involving risky decision-making, which correlates with higher rates of relapse.¹⁰⁸ Another study indicated that in a risky decision-making task, individuals who relapsed failed to show differentiated IC activation between safe and risky decisions, unlike those who maintained abstinence.¹⁰³ These findings support the involvement of the aIC in risk decision-making, enhancing reward processing in addiction while diminishing the cognitive evaluation of negative consequences. Altogether, these findings connect rat behaviors to human addiction patterns, further indicating the IC’s key role in risky decisions and relapse.

The precise contribution of the IC in decision-making related to risk-taking is still not fully understood. fMRI results suggest that the right IC is implicated in risky decision-making, and is partly modulated by individual variations in sensitivity to punishment.¹⁰⁹ In studies on risk-related neural activity, aIC neurons tend to exhibit increased activity for a longer duration following negative outcomes, with this increase being based on previously anticipated values.¹¹⁰ This implies that the aIC may be involved in processing the uncertainty and disappointment associated with rewards. Additionally, dopamine and serotonin have been identified as key neurotransmitters involved in risky decision-making, with some studies providing evidence to support their involvement in this process.^111,112,113 For instance, infusions of D1 receptor antagonists into the aIC increase impulsive decision-making in rodents in delayed discount tasks,¹¹² suggesting that increased DA signaling in the IC may drive risk-taking behavior. Conversely, intra-aIC infusions of D2 receptor antagonists and 5-hydroxytryptamine receptor 1A antagonists increase the risk response in gambling tasks in rodents based on the amplitude of water rewards.¹¹³ In summary, the IC influences individuals’ risk assessment and decision-making by integrating sensory and cognitive information. However, it is important to note that although these neural activations and neurotransmitter systems are associated with risk decision-making, further experimental validation is needed to establish a causal link between these neural changes and specific behaviors.

Motivation via the IC promotes addiction

SUD is viewed as a motivated behavior, with the initiation and maintenance of drug SA driven by the rewarding effects of drugs. The IC plays a crucial role in processing bodily-related signals and integrating them with external stimuli to modulate motivated behaviors. This effect is implicated in both regulatory processes of addictive behaviors and interoceptive processes that reflect the physical states associated with drug use.¹⁶ Neurons in the deep IC are connected to the NTS in the brainstem through a neural circuit. Activation of this circuit enhances licking behavior in mice, indicating an increase in motivation for reward, while its inhibition produces the opposite effects.¹⁵ Human neuroimaging studies have shown that the aIC is more active in tasks driven by intrinsic motivation than in non-motivational tasks.¹¹⁴ This indicates that the aIC is particularly involved in activities that require intrinsic drive and goal-directed behavior. Patients with IC injuries exhibit severe symptoms, including decreased motivation and reduced or absent nicotine cravings, suggesting that the IC may regulate dynamic-related behaviors.¹¹⁵ Evidence indicates that patients with subthreshold depression show higher activation of the left IC compared to controls when faced with greater monetary loss.¹¹⁶ This high activation is associated with motivational deficits and limited anticipatory pleasure, which are typical features of depression during SUD withdrawal. These findings suggest that IC dysfunction may be related to the motivational state following drug withdrawal. Thus, it is conceivable that dysfunction of the IC might be linked to depression and a motivational state following drug withdrawal. In conclusion, the IC is involved in the formation and regulation of drug-related motivation through its roles in processing motivation and responding to negative emotions. However, further research is needed to specify which behaviors are changing, what environmental events are involved, and how motivation is manifested behaviorally.

Conclusion

The IC promotes specific drug-related behaviors by linking intrinsic stimulation with drug use, such as increasing the frequency of drug intake and enhancing the reinforcing effects of drugs, which include increasing the duration of drug-induced euphoria and reducing the latency to drug-seeking behaviors.^8,35,70 These behaviors are often measured using a combination of self-report questionnaires assessing the frequency and intensity of drug use, and laboratory-based behavioral assays, such as the drug SA task, which measures the number of drug infusions obtained under different reinforcement schedules. During withdrawal, IC-mediated emotional learning sustains substance abuse by maintaining high levels of drug consumption and reducing the likelihood of abstinence,¹² thereby increasing the risk of relapse through negative reinforcement.⁷¹ Specifically, the IC is implicated in the negative reinforcement mechanisms that drive drug-seeking behaviors in response to withdrawal-induced aversive states.

The IC is critical for the formation and retrieval of drug memories, key elements to addictive behaviors.¹³ Studies show IC neural activity rises during the encoding and retrieval of these memories.^87,89 Additionally, the IC is involved in forming the associations between the drug and the relevant environment and cues and further participates in the consolidation and reconsolidation of drug memories, which can either promote or reduce drug taking. Drug memories’ consolidation and reconsolidation were assessed by the CPP paradigm, measuring time spent in different environments to evaluate drug-related memories.

In addition to its direct regulatory role, the IC also indirectly contributes to the development of SUD by influencing cognitive function, which can be assessed through specific cognitive tasks, showing a preference for high-risk, high-reward options.^103,108 It reflects impaired decision-making abilities. Compulsive drug use is a core feature of addiction, driven by motivation and maintenance. It prompts addicted individuals to seek drug pleasure or escape withdrawal pain. Strong cravings and relapse likelihood occur when facing drug cues or stress.¹¹⁷ These functional abnormalities are closely related to the maintenance and recurrence of addictive behaviors, making the IC an important target for the treatment of SUD.

Although the involvement of the IC in SUD is gradually being revealed, current research still has its limitations. Specifically, there is a translational gap between basic and clinical research. That is, rodent neurophysiological studies have not yet been linked to clinically relevant behaviors in addicted individuals. Although the IC has been demonstrated to regulate compulsive drug-seeking,³¹ its involvement in clinical SUD remains unclear. In addition, there are differences in research methodology. Basic research uses animal models and invasive techniques, including electrophysiology and optogenetics, to precisely observe and manipulate the activity of neurons. In contrast, clinical research relies on non-invasive techniques (neuroimaging) to observe changes in the structure and function of the IC. Thus, it is more difficult to establish causality in clinical research, and for this purpose, science heavily relies on animal research. However, the progress is slow due to the complexity of the IC circuitry and its multifunctionality.

The IC is a novel target for SUD treatment, as it regulates addictive behavior through interoception. Exploring how interoception modulates addictive behavior through IC and affects emotional and motivational responses is significant for addiction and related mental illness research. Transcranial deep brain stimulation (tDBS), a relatively mature technique for treating neurological diseases, offers potential for SUD treatment.¹¹⁸ Electrodes are placed in specific brain areas to regulate activity via electrical stimulation. This works by interrupting abnormal signals that interfere with normal neural activity, thus restoring normal neural communication. The IC stimulation may normalize pathological brain networks, as supported by a case in addiction treatment. There is evidence supporting this idea. For example, basic research has shown that in the rat SA, high-frequency electrical stimulation of the IC in rats significantly reduces nicotine intake and nicotine-seeking, compared to no stimulation of the IC.¹¹⁹ Clinical reports found that stroke patients with IC injury showed significant increases in smoking cessation, suggesting that lesions or inhibition of the IC might facilitate abstinence.¹²⁰ However, it should be noted that these findings are preliminary and do not directly translate into clinical treatment.

Future research should promote the integration of multiple technologies, combining fMRI, transcranial magnetic stimulation, tDCS, and other technologies, to reveal the role of the IC in SUD from multiple perspectives. The specific role of the IC in the comorbidity of SUD and other psychiatric disorders remains poorly understood. This is an area that warrants further investigation. Comorbid behaviors are defined by DSM-5 criteria and observed in clinical settings through assessments like interviews and observations. Functional distinctions from SUD-related behaviors are based on specific symptoms and mechanisms. A deeper understanding of the IC’s role in comorbidity can lead to the development of more effective treatments, improve therapeutic outcomes, and reduce relapse rates.

Data availability

All data generated or analyzed in this study are available from the corresponding author upon reasonable request.

Acknowledgments

This work was financially supported by the National Natural Science Foundation of China (grant no. 82271534). Any opinions, findings, conclusions, or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the previously stated funding agencies. The authors would like to thank BioRender.com for the charting.

Author contributions

Writing – original draft, D.T.; writing – review and editing, S.H., Z.S., J.W., and E.G.; writing – review and editing, funding acquisition, and conceptualization, Y.L.

Declaration of interests

The authors declare no competing interests.