Reinstatement Of Drug Seeking Research Articles

The activity-regulated cytoskeleton-associated protein, Arc, functions in the nucleus accumbens shell to limit multiple triggers of cocaine-seeking behaviour.

Use of addictive substances like cocaine produces enduring associations between the drug experience and cues in the drug-taking environment. In individuals with a substance use disorder (SUD) and attempting to remain abstinent, these powerful drug-cue associations can trigger a return to active drug use, but the molecular mechanisms regulating drug-cue associations remain poorly understood. The activity-regulated cytoskeleton-associated protein (Arc) is induced by cocaine in the nucleus accumbens (NAc), an important brain reward region, but Arc's NAc function in SUD-related behaviour remains unclear. We show here that cocaine self-administration (SA) in rats produced a significant upregulation of Arc protein in both the core and shell subregions of the NAc. Subregion-specific Arc reduction (shRNA) in the medial NAc Shell enhanced both context-associated and cue-reinstated cocaine seeking, but without altering the motivation to work for cocaine, the sensitivity to the reinforcing effects of cocaine or the ability of cocaine priming to reinstate drug seeking. In contrast, we observed no effects of Arc knockdown in the NAc core on any aspect of cocaine SA, extinction or reinstated cocaine seeking, suggesting that Arc functions within the medial NAc shell, but not NAc core, to limit the strength of drug-context and drug-cue associations that promote cocaine-seeking behaviour.

Relapse to cotinine seeking in rats: differential effects of sex.

Relapse is a defining feature of smoking and a significant challenge in cessation management. Elucidation of novel factors underlying relapse may inform future treatments. Cotinine, the major metabolite of nicotine, has been shown to support intravenous self-administration in rats, implicating it as one potential factor contributing to nicotine reinforcement. However, it remains unknown whether cotinine would induce relapse-like behaviors. The current study investigated relapse to cotinine seeking in two relapse models, the reinstatement of drug seeking and incubation of drug craving models. In the reinstatement model, rats were trained to self-administer cotinine, underwent extinction of cotinine-associated responses, and were tested for cue-, drug-, or stress-induced reinstatement. Conditioned cues associated with cotinine self-administration, cotinine (1-2 mg/kg), or the pharmacological stressor yohimbine (1.25-2.5 mg/kg) induced reinstatement of cotinine seeking. Female rats displayed more pronounced cue-induced, but not drug- or stress-induced reinstatement than male rats. In the incubation of the craving model, rats were trained to self-administer cotinine and underwent forced withdrawal in home cages. Rats were tested for cue-induced cotinine-seeking on both withdrawal day 1 and withdrawal day 18. Rats exhibited greater cue-induced cotinine-seeking on withdrawal day 18 compared to withdrawal day 1, with no difference between male and female rats. These findings indicate that cotinine induces sex-specific relapse to drug seeking in rats, suggesting that cotinine may contribute to relapse.

Ventral pallidum GABA neurons bidirectionally control opioid relapse across rat behavioral models

Opioid addiction is a chronic, relapsing disorder. Whether addicted individuals are forced to abstain or they decide themselves to quit using drugs, relapse rates are high—especially upon encountering contexts and stimuli associated with prior opioid use. Rodents similarly show context- and cue-induced reinstatement of drug seeking following abstinence, and intriguingly, the neural circuits underlying these relapse-like behaviors differ when abstinence is involuntarily imposed, responding is extinguished, or animals decide themselves to cease taking drug. Here, we employ two complementary rat behavioral models of relapse-like behavior for the highly reinforcing opioid drug remifentanil, and asked whether GABAergic neurons in the ventral pallidum (VPGABA) control opioid seeking under these behavioral conditions. Specifically, we asked how chemogenetically stimulating VPGABA neurons with clozapine-N-oxide (CNO) influences the ability of contextual or discrete remifentanil-paired cues to reinstate drug seeking following either voluntary abstinence (punishment-induced; GroupPunish), or extinction training (GroupExt). In GroupPunish rats, we also chemogenetically inhibited VPGABA neurons, and examined spontaneous VP activity (Fos) during cued reinstatement. In both GroupPunish and GroupExt rats, stimulating Gq-signaling in VPGABA neurons augmented remifentanil reinstatement in a cue- and context-dependent manner. Conversely, engaging inhibitory Gi-signaling in VPGABA neurons in GroupPunish suppressed cue-induced reinstatement, and cue-triggered seeking was correlated with Fos expression in rostral, but not caudal VP. Neither stimulating nor inhibiting VPGABA neurons influenced unpunished remifentanil self-administration. We conclude that VPGABA neurons bidirectionally control opioid seeking regardless of the specific relapse model employed, highlighting their fundamental role in opioid relapse-like behavior across behavioral models, and potentially across species.

Morinda citrifolia Linn. fruit extract mitigates heroin seeking behavior in mice

Methanolic extract of Morinda citrifolia unripe fruit (MMC) was tested against heroin addiction using a mouse modified runway model of drug‑seeking. Habituation sessions were carried out for 10 min/d for 3 days. On day 0, the total run time of each mouse was noted (the start box to goal box) during the preconditioning test. This was followed by the conditioning session (30 min), in which the animals were conditioned with escalating doses of heroin hydrochloride (5, 10, 20, 40 and 40 mg/kg) for 5 days upon entry into the goal box. On day 6, the run time of each mouse, from start to goal box, was recorded during the post conditioning test. Extinction trials were performed for the next 5 days, in which no drug/saline was injected upon goal box entry. On day 13, a priming dose of heroin (8 mg/kg) was given to reinstate drug seeking in the mice. MMC given as oral doses (1, 3 and 5 g/kg) dose‑dependently prolonged the run time to reach the goal box, indicating MMC attenuated heroin reinforcement. Moreover, MMC (5 g/kg) was found to reverse the heroin‑seeking on extinction trial 1 and 2. MMC was also found to reverse heroin‑induced reinstatement in mice. This study demonstrates that MMC attenuated heroin seeking at different phases of drug self‑administration in a mouse modified runway model.

Disrupting Reconsolidation by Systemic Inhibition of mTOR Kinase via Rapamycin Reduces Cocaine-Seeking Behavior.

Drug addiction is considered maladaptive learning, and drug-related memories aroused by the presence of drug related stimuli (drug context or drug-associated cues) promote recurring craving and reinstatement of drug seeking. The mammalian target of rapamycin signaling pathway is involved in reconsolidation of drug memories in conditioned place preference and alcohol self-administration (SA) paradigms. Here, we explored the effect of mTOR inhibition on reconsolidation of addiction memory using cocaine self-administration paradigm. Rats received intravenous cocaine self-administration training for 10 consecutive days, during which a light/tone conditioned stimulus was paired with each cocaine infusion. After acquisition of the stable cocaine self-administration behaviors, rats were subjected to nosepoke extinction (11 days) to extinguish their behaviors, and then received a 15 min retrieval trial with or without the cocaine-paired tone/light cue delivery or without. Immediately or 6 h after the retrieval trial, rapamycin (10 mg/kg) was administered intraperitoneally. Finally, cue-induced reinstatement, cocaine-priming-induced reinstatement and spontaneous recovery of cocaine-seeking behaviors were assessed in rapamycin previously treated animals, respectively. We found that rapamycin treatment immediately after a retrieval trial decreased subsequent reinstatement of cocaine seeking induced by cues or cocaine itself, and these effects lasted at least for 28 days. In contrast, delayed intraperitoneal injection of rapamycin 6 h after retrieval or rapamycin injection without retrieval had no effects on cocaine-seeking behaviors. These findings indicated that mTOR inhibition within the reconsolidation time-window impairs the reconsolidation of cocaine associated memory, reduces cocaine-seeking behavior and prevents relapse, and these effects are retrieval-dependent and temporal-specific.

Exploring the role of the Ser9Gly (rs6280) Dopamine D3 receptor polymorphism in nicotine reinforcement and cue-elicited craving

Preclinical studies show that the dopamine D3 receptor (D3R) is involved in the reinstatement of drug seeking and motivation for drugs of abuse. A D3R gene variant, Ser9Gly (rs6280) has been linked to nicotine dependence, yet the mechanisms underlying its involvement in nicotine dependence is unclear. This study investigated the relationship between the Ser9Gly variant and measures of both nicotine reinforcement and cue-elicited craving. Phenotypes of smoking behaviors were assessed in genetically grouped (Glycine vs. No Glycine carriers) current smokers (n = 104, ≥ 10 cigarettes per day). Laboratory measures included a forced choice session (to measure reinforcement of nicotine containing vs. denicotinized cigarettes), and a cue-reactivity session (to measure smoking cues vs. neutral cues elicited craving). The forced choice procedure revealed that subjective ratings were significantly higher in response to nicotinized compared to denicotinized cigarettes; however the Ser9Gly variant did not influence this effect. By comparison, smoking cues elicited greater craving over time compared to neutral cues, and Glycine carriers of the Ser9Gly D3R variant seem to experience a significant blunted cue-elicited craving effect. Results support D3R involvement in nicotine cue reactivity. However, more research is needed to reveal how this gene variant modulates various aspects of nicotine dependence.

Unpleasant sound elicits negative emotion and reinstates drug seeking

Unpleasant sound elicits negative emotion and reinstates drug seeking

N-Acetylcysteine treatment during acute stress prevents stress-induced augmentation of addictive drug use and relapse.

Converging epidemiological studies show that a life-threatening event increases the incidence of posttraumatic stress disorder (PTSD), which carries 30% to 50% comorbidity with substance use disorders (SUDs). Such comorbidity results in greater drug use and poorer treatment outcomes. There is overlap between the enduring synaptic neuroadaptations produced in nucleus accumbens core (NAcore) by acute restraint stress and cocaine self-administration. Because of these coincident neuroadaptations, we hypothesized that an odor paired with acute restraint stress would reinstate drug seeking and chose two mechanistically distinct drugs of abuse to test this hypothesis: alcohol and cocaine. Rats were trained to self-administer either drug beginning 3 weeks after odor pairing with acute stress or sham, and acute restraint stress increased alcohol consumption. Following context extinction training, the stress-paired odor reinstated both alcohol and cocaine seeking, while an unpaired odor had no effect. N-Acetylcysteine (NAC) restores drug and stress-induced reductions in glial glutamate transporter-1 and has proven effective at reducing cue-induced reinstatement of drug seeking. We administered NAC for 5 days prior to reinstatement testing and abolished the capacity of the stress-paired odor to increase alcohol and cocaine seeking. Importantly, daily NAC given during or just following experiencing acute restraint stress also prevented the capacity of stress-paired odors to reinstate alcohol and cocaine seeking and prevented stress-induced deficits in behavioral flexibility. These data support using daily NAC treatment during or immediately after experiencing a strong acute stress to prevent subsequent conditioned stress responding, in particular relapse and cognitive deficits induced by stress-conditioned stimuli.

Unpleasant Sound Elicits Negative Emotion and Reinstates Drug Seeking.

Although previous studies have suggested an association between unpleasant sounds and the use of drugs, scientific evidence supporting this is lacking. This study investigated in rats (male Sprague-Dawley rats) if aversive sounds modulate dopamine (DA) transmission in the mesolimbic reward system and cocaine reinforcement. For sound stimulation, we used artificial low-frequency ultrasound (ALFUS) in the frequency ranges (22-38kHz) which produces an aversive response in rats. Rats displayed increased anxiety-like behaviors, 22-kHz ultrasonic vocalizations (USVs), and stress responses with ALFUS. In vivo extracellular recording and immunohistochemistry revealed that ALFUS stimulation activated central amygdalar neurons and amygdalar GABAergic neurons. Amygdalar lesions prevented an increase of 22-kHz USVs by ALFUS. Dopamine levels in NAc decreased during ALFUS stimulation. In rats self-administering cocaine, ALFUS caused reinstatement of cocaine seeking after a period of extinction. Thus, ALFUS stimulation induced negative emotional states in association with a decrease in mesolimbic DA function and reinstatement of cocaine-seeking behaviors, suggesting that exposure to unpleasant sounds enhances negative emotional states and may induce relapse in addicts.

Transient synaptic potentiation in nucleus accumbens shell during refraining from cocaine seeking.

Repeated exposure to drug-associated cues without reward (extinction) leads to refraining from drug seeking in rodents. We determined if refraining is associated with transient synaptic plasticity (t-SP) in nucleus accumbens shell (NAshell), akin to the t-SP measured in the NAcore during cue-induced reinstatement of drug seeking. Using whole cell patch electrophysiology, we found that medium spiny neurons (MSNs) in NAshell expressed increased ratio of AMPA to NMDA glutamate receptor currents during refraining, which normalized to baseline levels by the end of the 2-hour extinction session. Unlike t-SP observed in NAcore during reinstated drug seeking, neither dendrite spine head enlargement nor activation of matrix metalloproteases (MMP2/9) accompanied the increased AMPA:NMDA in NAshell during refraining. Refraining was also not associated with changes in paired pulse ratio, NMDA receptor current decay time, or AMPA receptor rectification index in NAshell MSNs. Our preliminary data in transgenic mice suggest that t-SP may increase D2-MSN inputs relative to D1-MSN inputs.

Structurally Similar and Behaviorally Unique Modafinil Analogs as Potential Pharmacotherapeutics for Psychostimulant Use Disorder

Modafinil has been used off‐label to treat psychostimulant use disorders (PSUD). However, its effectiveness in clinical trials seems limited to a subpopulation of subjects without concurrent alcohol or poly‐drug use. Since the main pharmacological target of cocaine is the dopamine transporter (DAT), recent efforts to develop more globally effective pharmacotherapies for PSUD have focused on two new DAT inhibitors and structural analogs of modafinil, JJC8‐088 and JJC8‐091, as promising lead compounds.In this study, the behavioral effects of these compounds were tested in rat models of cocaine self‐administration and reinstatement to drug seeking. Neurochemical correlates to those behaviors were assessed in microdialysis and fast‐scan cyclic voltammetry (FSCV) procedures aimed to measure extracellular dopamine levels and potential changes in dopamine dynamics in the nucleus accumbens shell (NAS).Our results show that JJC8‐088 (3, 10, 30 mg/kg, i.p.) dose‐dependently decreased the number of cocaine infusions under a fixed ratio schedule of self‐administration, while JJC8‐091 (10, 30, 56 mg/kg) failed to significantly alter cocaine self‐administration. In contrast, JJC8‐088 failed, while JJC8‐091 effectively decreased the break‐point for cocaine self‐administration under a progressive ratio schedule of behavior. JJC8‐088 maintained self‐administration behavior in both drug‐naïve and cocaine trained rats, while JJC8‐091 did not. Moreover, only priming injections of JJC8‐088 dose‐dependently reinstated drug‐seeking behavior in rats following previous cocaine extinction. Importantly, in the same rats, JJC8‐091 pretreatment blocked cocaine‐induced reinstatement of drug seeking behavior.The neurochemical assessment of JJC8‐088 and JJC8‐091 effects showed that both drugs dose‐dependently increased extracellular DA concentrations in dialysates from the NAS. However, JJC8‐088 was more potent and more efficacious in increasing DA levels compared to JJC8‐091. Indeed, the maximal changes in DA levels elicited by JJC8‐088 resemble those obtained with cocaine, in contrast to JJC8‐091.The FSCV studies showed that both JJC8‐088 and JJC8‐091 dose dependently reduced the rate of DA clearance, with JJC8‐088 producing effects greater in magnitude at lower doses than JJC8‐091. Finally, like cocaine, cumulative doses of JJC8‐088 produced a dose‐dependent increase in DAMax, while JJC8‐091 was ineffective at all doses tested.Collectively, these data show that despite sharing significant structural similarity, JJC8‐088 was cocaine‐like, while JJC8‐091 was not. Indeed, in contrast with JJC8‐088, JJC8‐091 did not elicit significant reinforcing actions and reduced or blunted the reinforcing effects of cocaine. Taken together, our data support further development of JJC8‐091, as a potential pharmacotherapy for the treatment of PSUD.Support or Funding InformationSupport for this research was provided by the Medication Development Program, National Institute on Drug Abuse ‐ Intramural Research Program, NIH/DHHSThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Social reinstatement: a rat model of peer-induced relapse.

An important factor that can lead to drug relapse is to re-associate with drug-using social peers, but there is little literature on the effect of social peers on relapse in animal models. The current study used a dual-compartment operant conditioning apparatus that allowed adult male rats to respond for cocaine in the presence of a conspecific. In experiment 1, rats were trained to self-administer cocaine in the presence of a social peer that was separated by a wire screen partition and then that peer was used as a reinstatement cue following a period of extinction. In the next experiments, rats were trained on alternating sessions to self-administer cocaine in the presence of one peer and to self-administer saline in the presence of a different peer using either a single-active lever procedure (experiment 2) or a double-active lever procedure (experiment 3). Following extinction of responding in the absence of the peers, the effect of re-exposure to the cocaine- and saline-associated peers on reinstatement of drug seeking was determined. This was tested using both single- and double-active lever procedures. In experiment 1, a peer that was present throughout cocaine self-administration was able to reinstate cocaine seeking following a period of extinction. In experiments 2 and 3, drug seeking was reinstated by the cocaine-associated peer (S+), but not the saline-associated peer (S-). This discrimination occurred when using either the single-active lever procedure or double-active lever procedure. These results indicate that a social peer can be used as a discriminative stimulus to signal cocaine availability and that re-introduction of a peer previously paired with cocaine can reinstate cocaine seeking, confirming clinical reports that peer affiliation among abstinent cocaine users is an important determinant of relapse.

The nucleus accumbens shell in reinstatement and extinction of drug seeking.

The contexts where drugs are self-administered have important control over relapse and extinction of drug-seeking behavior. The nucleus accumbens shell (AcbSh) is essential to this contextual control over drug-seeking behavior. It has been consistently implicated in both the expression of context-induced reinstatement and the expression of extinction, across a variety of drug classes and other rewards. Here, we review the evidence linking AcbSh to the extinction and reinstatement of drug seeking. We consider whether this dual role can be linked to known heterogeneities in AcbSh cell types, their major afferents, and their major efferents. We show that although these heterogeneities are each important and can determine extinction vs. reinstatement, they do not seem adequate to explain the body of findings from the behavioral literature. Rather, we suggest that this functional specialization of AcbSh may be more profitably viewed in terms of the segregation and compartmentalization of AcbSh channels.

Reinstatement of Drug-seeking in Mice Using the Conditioned Place Preference Paradigm.

The present protocol describes the Conditioned Place Preference (CPP) as a model of relapse in drug addiction. In this model, animals are first trained to acquire a conditioned place preference in a drug-paired compartment, and after the post-conditioning test, they perform several sessions to extinguish the established preference. The CPP permits the evaluation of the conditioned rewarding effects of drugs related to environmental cues. Then, the extinguished CPP can be robustly reinstated by the non-contingent administration of a priming dose of the drug, and by exposure to stressful stimuli. Both methods will be explained here. When the animal reinitiates the behavioral response, a reinstatement of the conditioned reward is considered to have taken place. The main advantages of this protocol are that it is non-invasive, inexpensive, and simple with good validity criteria. In addition, it allows the study of different environmental manipulations, such as stress or diet, which can modulate relapse into drug seeking behaviors. However, one limitation is that if the researcher aims to explore the motivation and primary reinforcing effects of the drug, it should be complemented with self-administration procedures, as they involve operant responses of animals.

Reinstatement of Drug-seeking in Mice Using the Conditioned Place Preference Paradigm

Reinstatement of Drug-seeking in Mice Using the Conditioned Place Preference Paradigm

A Model of Δ9-Tetrahydrocannabinol Self-administration and Reinstatement That Alters Synaptic Plasticity in Nucleus Accumbens

BackgroundCannabis is the most widely used illicit drug, but knowledge of the neurological consequences of cannabis use is deficient. Two primary components of cannabis are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). We established a THC+CBD model of self-administration and reinstated drug seeking to determine if, similar to other addictive drugs, cannabis produces enduring synaptic changes in nucleus accumbens core (NAcore) thought to contribute vulnerability to drug reinstatement. MethodsSprague Dawley rats were trained to self-administer THC+CBD (n = 165) or were used as vehicle self-administering control animals (n = 24). Reinstatement was initiated by context, cues, drug priming, and stress (yohimbine injection). Enduring neuroadaptations produced by THC+CBD self-administration were assayed using four measures: dendritic spine morphology, long-term depression, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/N-methyl-D-aspartate ratios, and behavioral pharmacology. ResultsWe described a novel rodent model of cannabis relapse involving intravenous THC+CBD self-administration and drug seeking induced by conditioned context, cues, and stress. Cued reinstatement of THC+CBD seeking depended on a sequence of events implicated in relapse to other addictive drugs, as reinstatement was prevented by daily treatment with N-acetylcysteine or acute intra-NAcore pretreatment with a neuronal nitric oxide synthase or matrix metalloprotease-9 inhibitor, all of which normalize impaired glutamate homeostasis. The capacity to induce N-methyl-D-aspartate long-term depression in NAcore medium spiny neurons was abolished and dendritic spine density was reduced, but alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/N-methyl-D-aspartate ratio was unaltered in THC+CBD-trained animals, akin to opioids, but not to psychostimulants. ConclusionsWe report enduring consequences of THC+CBD use on critical relapse circuitry and synaptic physiology in NAcore following rat self-administration and provide the first report of cue- and stress-induced reinstatement with this model.

F262. Modeling Opioid Maintenance Therapy in Rats: Effect of Chronic Buprenorphine on Responding for Drug-Paired Discrete Cues in a Non-Drug Context, Context-Induced Reinstatement of Drug Seeking, and Reacquisition of Oxycodone Self-Administration

F262. Modeling Opioid Maintenance Therapy in Rats: Effect of Chronic Buprenorphine on Responding for Drug-Paired Discrete Cues in a Non-Drug Context, Context-Induced Reinstatement of Drug Seeking, and Reacquisition of Oxycodone Self-Administration

The Winding Road to Relapse: Forging a New Understanding of Cue-Induced Reinstatement Models and Their Associated Neural Mechanisms.

In drug addiction, cues previously associated with drug use can produce craving and frequently trigger the resumption of drug taking in individuals vulnerable to relapse. Environmental stimuli associated with drugs or natural reinforcers can become reliably conditioned to increase behavior that was previously reinforced. In preclinical models of addiction, these cues enhance both drug self-administration and reinstatement of drug seeking. In this review, we will dissociate the roles of conditioned stimuli as reinforcers from their modulatory or discriminative functions in producing drug-seeking behavior. As well, we will examine possible differences in neurobiological encoding underlying these functional differences. Specifically, we will discuss how models of drug addiction and relapse should more systematically evaluate these different types of stimuli to better understand the neurobiology underlying craving and relapse. In this way, behavioral and pharmacotherapeutic interventions may be better tailored to promote drug use cessation outcomes and long-term abstinence.

Accumbens Mechanisms for Cued Sucrose Seeking

Many studies support a perspective that addictive drugs usurp brain circuits used by natural rewards, especially for the dopamine-dependent reinforcing qualities of both drugs and natural rewards. Reinstated drug seeking in animal models of relapse relies on glutamate spillover from cortical terminals synapsing in the nucleus accumbens core (NAcore) to stimulate metabotropic glutamate receptor5 (mGluR5) on neuronal nitric oxide synthase (nNOS) interneurons. Contrasting the release of dopamine that is shared by sucrose and drugs of abuse, reinstated sucrose seeking does not induce glutamate spillover. We hypothesized that pharmacologically promoting glutamate spillover in the NAcore would mimic cocaine-induced adaptations and potentiate cued reinstatement of sucrose seeking. Inducing glutamate spillover by blocking astroglial glutamate transporters (GLT-1) had no effect on reinstated sucrose seeking. However, glutamate release probability is negatively regulated by presynaptic mGluR2/3, and sucrose reinstatement was potentiated following mGluR2/3 blockade. Potentiated sucrose reinstatement by mGluR2/3 blockade was reversed by antagonizing mGluR5, but reinstated sucrose seeking in the absence of mGluR2/3 blockade was not affected by blocking mGluR5. In cocaine-trained rodents mGluR5 stimulation reinstates drug seeking by activating nNOS, but activating mGluR5 did not promote reinstated sucrose seeking, nor was potentiated reinstatement after mGluR2/3 blockade reduced by blocking nNOS. However, chemogenetic activation of nNOS interneurons in the NAcore reinstated sucrose seeking. These data indicate that dysregulated presynaptic mGluR2/3 signaling is a possible site of shared signaling in drug seeking and potentiated reinstated sucrose seeking, but that downregulated glutamate transport and subsequent activation of nNOS by synaptic glutamate spillover is not shared.

Revisiting the role of the insula and smoking cue-reactivity in relapse: A replication and extension of neuroimaging findings

IntroductionThe ability to direct smoking cessation treatment based on neuroscientific findings holds incredible promise. However, there is a strong need for consistency across studies to confirm neurobiological targets. While our prior work implicated enhanced insula reactivity to smoking cues in tobacco smoking relapse vulnerability, this finding has not been confirmed. MethodUsing functional magnetic resonance imaging (fMRI), we evaluated the pre-cessation brain reactivity to smoking vs. neutral cues in nicotine dependent smokers who were and were not able to maintain subsequent abstinence. ResultsOf the 23 (7 women) individuals assessed, 13 relapsed and there were no demographic differences between those who did and did not relapse. However, smokers who relapsed showed enhanced reactivity to smoking cues in the right insula and dorsal striatum, showing significant overlap between our current and prior work despite methodological differences, including the fact that our previous work only included women. ConclusionThe current work supports our prior results and builds on the concept that the insula and dorsal striatum work in concert to maintain nicotine dependence. Specifically, dorsal striatal-mediated habitual responding may be triggered both by the external drug-associated cues, and the insula-mediated internal states that provide additional context motivating drug use. This replicated finding also mirrors preclinical work that finds the same individualized distinction, as only some rodents attribute incentive salience to drug cues and are more likely to reinstate drug seeking after extinction. To effectively treat addiction, these individual characteristics and their underlying neurobiological foundations must be considered.