Cocaine Cues Research Articles

Psilocybin administered following extinction sessions does not affect subsequent cocaine cue reinstatement in male and female rats and mice

There are currently no pharmacological treatments for cocaine use disorder. Recently there has been a great deal of interest in the potential of psychedelic drugs such as psilocybin to treat psychiatric disorders. Human studies have indicated that a single administration of psilocybin can have long-lasting effects. Few preclinical studies have examined a role for psilocybin in addiction models. The goal of the current study was to determine whether psilocybin would enhance extinction following cocaine self-administration in male and female mice and rats and thus result in an attenuation of cue-induced drug-seeking. In experiments in mice, 16 female and 19 male mice underwent 8d of cocaine self-administration (0.5 mg/kg/infusion) and extinction training. Immediately following extinction trials, mice were injected with vehicle or 1.0 mg/kg psilocybin. Following the conclusion of extinction training, mice were tested for cue-induced reinstatement. In experiments in rats, 24 female and 23 male rats underwent 15d of cocaine self-administration (0.8 mg/kg/infusion) and extinction training. Immediately following extinction trials, rats were injected with vehicle, 1.0 mg/kg psilocybin, or 2.5 mg/kg psilocybin. Following the conclusion of extinction training, rats were tested for cue-induced reinstatement. Psilocybin administered following extinction trials had no effect, as both female and male mice and rats demonstrated significant cue-induced reinstatement. These data suggest that psilocybin is ineffective at altering cocaine-seeking behavior in the paradigm and doses used in the current study. It remains to be seen whether treatment with psilocybin under different conditions may be useful in the long-standing goal of finding pharmacotherapies to treat CUD.

Virtual reality cue-exposure therapy in reducing cocaine craving: the Promoting Innovative COgnitive behavioral therapy for Cocaine use disorder (PICOC) study protocol for a randomized controlled trial

BackgroundCocaine craving is a central symptom of cocaine use disorders (CUD). Virtual reality cue-exposure therapy for craving (VRCET) allows more immersive, realistic, and controllable exposure than traditional non-VR cue-exposure therapy (CET), whose efficacy is limited in treating substance use disorders. The purpose of this study is to evaluate the efficacy and acceptability of VRCET, as a stand-alone and add-on intervention (i.e., combined with cognitive therapy), compared to a picture-based CET (PCET), in reducing self-reported cocaine craving in inpatients hospitalized for CUD.MethodsFifty-four inpatients hospitalized for CUD will be randomized in one of two intensive 3-week treatment arms: 10 meetings/2-week treatment of VRCET plus 5 meetings/1-week treatment of memory-focused cognitive therapy (MFCT; experimental arm), or 15 meetings/3-week treatment of PCET (active control arm). The Craving Experience Questionnaire (CEQ – F & S) will be used to assess the primary outcome, i.e., the post-treatment decrease of self-reported cocaine craving frequency (within the past 2 weeks) and intensity scores (in VR exposure to cocaine cues). Secondary endpoints include urinary, physiological, and self-reported cocaine use-related measures. Assessments are scheduled at pretreatment, after 2 weeks of treatment (i.e., VRCET vs. PCET), post-treatment (3 weeks, i.e., VRCET + MFCT vs. PCET), and at 1-month follow-up. Acceptability will be evaluated via (i) the Spatial Presence for Immersive Environments – Cybersickness along VRCET and (ii) the Client Satisfaction Questionnaires after 2 weeks of treatment and post-treatment.DiscussionThis study will be the first to evaluate the acceptability and efficacy of VRCET for CUD, as a psychotherapeutic add-on, to reduce both cocaine craving frequency and intensity. Additionally, this study will provide evidence about the specific interest of VRCET, compared to a non-VR-based CET, as a cue reactivity and exposure paradigm for treating substance use disorders.Trial registrationNCT05833529 [clinicaltrials.gov]. Prospectively registered on April 17, 2023.

Social context and drug cues modulate inhibitory control in cocaine addiction: involvement of the STN evidenced through functional MRI.

Addictions often develop in a social context, although the influence of social factors did not receive much attention in the neuroscience of addiction. Recent animal studies suggest that peer presence can reduce cocaine intake, an influence potentially mediated, among others, by the subthalamic nucleus (STN). However, there is to date no neurobiological study investigating this mediation in humans. This study investigated the impact of social context and drug cues on brain correlates of inhibitory control in individuals with and without cocaine use disorder (CUD) using functional Magnetic Resonance Imaging (fMRI). Seventeen CUD participants and 17 healthy controls (HC) performed a novel fMRI "Social" Stop-Signal Task (SSST) in the presence or absence of an observer while being exposed to cocaine-related (vs. neutral) cues eliciting craving in drug users. The results showed that CUD participants, while slower at stopping with neutral cues, recovered control level stopping abilities with cocaine cues, while HC did not show any difference. During inhibition (Stop Correct vs Stop Incorrect), activity in the right STN, right inferior frontal gyrus (IFG), and bilateral orbitofrontal cortex (OFC) varied according to the type of cue. Notably, the presence of an observer reversed this effect in most areas for CUD participants. These findings highlight the impact of social context and drug cues on inhibitory control in CUD and the mediation of these effects by the right STN and bilateral OFC, emphasizing the importance of considering the social context in addiction research. They also comfort the STN as a potential addiction treatment target.

Sex-Dependent Differences in the Neural Correlates of Cocaine and Emotional Cue-Reactivity in Regular Cocaine Users and Non-Drug-Using Controls: Understanding the Role of Duration and Severity of Use

Introduction: The development of cocaine use disorder in females is suggested to be more strongly related to neural mechanisms underlying stress-reactivity, whereas in males it is suggested to be more strongly related to neural mechanisms underlying drug cue-reactivity. Existing evidence, however, is based on neuroimaging studies that either lack a control group and/or have very small sample sizes that do not allow to investigate sex differences. Methods: The main objective of the current study was to investigate sex differences in the neural correlates of cocaine and negative emotional cue-reactivity within high-risk intranasal cocaine users (CUs: 31 males and 26 females) and non-cocaine-using controls (non-CUs: 28 males and 26 females). A region of interest (ROI) analysis was applied to test for the main and interaction effects of group, sex, and stimulus type (cocaine cues vs. neutral cocaine cues and negative emotional cues vs. neutral emotional cues) on activity in the dorsal striatum, ventral striatum (VS), amygdala, and dorsal anterior cingulate cortex (dACC). Results: There were no significant sex or group differences in cocaine cue-reactivity in any of the ROIs. Results did reveal significant emotional cue-reactivity in the amygdala and VS, but these effects were not moderated by group or sex. Exploratory analyses demonstrated that emotional cue-induced activation of the dACC and VS was negatively associated with years of regular cocaine use in female CUs, while this relationship was absent in male CUs. Conclusions: While speculative, the sex-specific associations between years of regular use and emotional cue-reactivity in the dACC and VS suggest that, with longer years of use, female CUs become less sensitive to aversive stimuli, including the negative consequences of cocaine use, which could account for the observed “telescoping effect” in female CUs.

Towards virtual reality exposure therapy for cocaine use disorder: A feasibility study of inducing cocaine craving through virtual reality

BackgroundCraving is a core symptom of cocaine use disorders (CUD). Inducing craving in exposure to substance cues is of relevant interest for numerous clinical applications. Virtual reality exposure (VRE) might be a promising candidate for improving cue-exposure paradigms but remains almost not studied for cocaine. This feasibility study’s main aim is to assess whether VRE to cocaine cues is capable to induce cocaine craving compared with VRE to neutral cues. MethodsWe conducted a within-subjects controlled trial in which cocaine users performed 3 consecutive 10 mins-tasks: VRE to neutral and cocaine cues, and a relaxation-based resting procedure. The primary outcome was the change in Cocaine Craving Questionnaire-Brief (CCQ-Brief) scores between VRE to neutral and cocaine cues. Secondary outcomes included between-tasks changes in scores of cocaine craving, pleasant/unpleasant emotions as well as self-efficacy to cope with craving. ResultsWe recruited 11 chronic cocaine users including mostly crack smokers (45 %), cocaine snorters (36 %) and injectors (18 %), with 73 % of participants meeting DSM-IV criteria for cocaine dependence and/or abuse. Non-parametrical sign tests indicated significant large increases of CCQ-Brief scores from neutral to cocaine cue-VRE (S(11) = 11, p < 0.01, Cliff’s Δ = 0.65, 95 % CI: 0.17–0.88). Exploratory comparative analyses indicated significant changes after our post-cues VRE relaxation procedure, with cocaine craving and emotions restored to baseline. ConclusionsVRE to cocaine cues was feasible and capable to induce cocaine craving in cocaine users. This second VRE-based cue-reactivity study in cocaine paves the way for unexplored research on VRE clinical applications for CUD.

Intrinsic connectivity demonstrates a shared role of the posterior cingulate for cue reactivity in both gambling and cocaine use disorders

Cue reactivity is relevant across addictive disorders as a process relevant to maintenance, relapse, and craving. Understanding the neurobiological foundations of cue reactivity across substance and behavioral addictions has important implications for intervention development. The present study used intrinsic connectivity distribution methods to examine functional connectivity during a cue-exposure fMRI task involving gambling, cocaine and sad videos in 22 subjects with gambling disorder, 24 with cocaine use disorder, and 40 healthy comparison subjects. Intrinsic connectivity distribution implicated the posterior cingulate cortex (PCC) at a stringent whole-brain threshold. Post-hoc analyses investigating the nature of the findings indicated that individuals with gambling disorder and cocaine use disorder exhibited decreased connectivity in the posterior cingulate during gambling and cocaine cues, respectively, as compared to other cues and compared to other groups. Brain-related cue reactivity in substance and behavioral addictions involve PCC connectivity in a content-to-disorder specific fashion. The findings suggesting that PCC-related circuitry underlies cue reactivity across substance and behavioral addictions suggests a potential biomarker for targeting in intervention development.

Mapping the Neural Substrates of Cocaine Craving: A Systematic Review.

Craving is one of the most important symptoms of cocaine use disorder (CUD) since it contributes to the relapse and persistence of such disorder. This systematic review aimed to investigate which brain regions are modulated during cocaine craving. The articles were obtained through searches in the Google Scholar, Regional BVS Portal, PubMed, and Scielo databases. Overall, there was a selection of 36 studies with 1574 individuals, the majority being participants with CUD, whereby about 61.56% were individuals with CUD and 38.44% were controls (mean age = 40.4 years). Besides the methodological points, the neurobiological investigations comprised fMRI (58.34%) and PET (38.89%). The induction of cocaine craving was studied using different methods: exposure to cocaine cues (69.45%), stressful stimuli, food cues, and methylphenidate. Brain activations demonstrated widespread activity across the frontal, parietal, temporal, and occipital lobes, basal ganglia, diencephalon, brainstem, and the limbic system. In addition to abnormalities in prefrontal cortex activity, abnormalities in various other brain regions' activity contribute to the elucidation of the neurobiology of cocaine craving. Abnormalities in brain activity are justified not only by the dysfunction of dopaminergic pathways but also of the glutamatergic and noradrenergic pathways, and distinct ways of inducing craving demonstrated the involvement of distinct brain circuits and regions.

Attentional biases in abstinent patients with cocaine use disorder: rapid orienting or delayed disengagement?

Addiction-related attentional biases may play a central role in the development and maintenance of drug-seeking and drug-taking behaviors. However, evidence in cocaine dependence is limited and mixed. This study examined the time course and component processes of attentional biases for cocaine-related cues in a sample of 47 outpatients (38 men) with cocaine use disorder (CUD) with varying durations of current abstinence. Reaction times in a visual dot-probe task with two picture exposure durations -500 ms, to assess initial stages of attention, and 2,000 ms, to assess maintained attention- were recorded. We found faster responses to probes replacing cocaine-related vs. matched control pictures in the 500 ms but not in the 2,000 ms condition, indicative of early but not late attentional biases for cocaine cues in abstinent patients with CUD. Further comparisons with a neutral baseline revealed that it was not due to rapid orienting but to delayed disengagement from cocaine-related pictures, being this effect greater the longer the period of current abstinence. Consistent with the incentive-sensitization theory, these data suggest that cocaine-related stimuli maintain the capacity to hold spatial attention in abstinent patients with CUD, even after months of abstinence, highlighting the relevance of carrying out stimulus control to avoid relapses.

Assessing cocaine motivational value: Comparison of brain reactivity bias toward cocaine cues and cocaine demand.

The behavioral economic measure drug demand and the neural measure late positive potential (LPP) are two measures of motivational value that have been associated with drug relapse risk and treatment outcomes. Despite having overlapping themes, no studies have directly compared drug demand and LPP. Participants (N = 59) included treatment-seeking individuals with cocaine use disorder that had completed both a baseline cocaine demand task and an electroencephalogram (EEG) picture-viewing task of drug-related and pleasant picture cues. Associations between the LPP difference score amplitude (drug-pleasant) and five demand indices (Q₀, essential value [EV], Omax, Pmax, and breakpoint [BP]) were evaluated via Bayesian generalized linear modeling. Positive associations (posterior probabilities ≥ 75%) were found between LPP amplitude and four demand indices (Q₀, EV, Omax, BP). These results suggest that individuals who attach greater relevance to cocaine cues also exhibit greater valuation of cocaine reward. Implications for incorporating methodology from behavioral science and brain imaging are discussed. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Heightened cocaine-seeking in male rats associates with a distinct transcriptomic profile in the medial prefrontal cortex.

Drug overdose deaths involving cocaine have skyrocketed, an outcome attributable in part to the lack of FDA-approved medications for the treatment of cocaine use disorder (CUD), highlighting the need to identify new pharmacotherapeutic targets. Vulnerability to cocaine-associated environmental contexts and stimuli serves as a risk factor for relapse in CUD recovery, with individual differences evident in the motivational aspects of these cues. The medial prefrontal cortex (mPFC) provides top-down control of striatal circuitry to regulate the incentive-motivational properties of cocaine-associated stimuli. Clinical and preclinical studies have identified genetic variations that impact the degree of executive restraint over drug-motivated behaviors, and we designed the present study to employ next-generation sequencing to identify specific genes associated with heightened cue-evoked cocaine-seeking in the mPFC of male, outbred rats. Rats were trained to stably self-administer cocaine, and baseline cue-reinforced cocaine-seeking was established. Rats were phenotyped as either high cue (HC) or low cue (LC) responders based upon lever pressing for previously associated cocaine cues and allowed 10 days of abstinence in their home cages prior to mPFC collection for RNA-sequencing. The expression of 309 genes in the mPFC was significantly different in HC vs. LC rats. Functional gene enrichment analyses identified ten biological processes that were overrepresented in the mPFC of HC vs. LC rats. The present study identifies distinctions in mPFC mRNA transcripts that characterizes individual differences in relapse-like behavior and provides prioritized candidates for future pharmacotherapeutics aimed to help maintain abstinence in CUD. In particular the Htr2c gene, which encodes the serotonin 5-HT2C receptor (5-HT2CR), is expressed to a lower extent in HC rats, relative to LC rats. These findings build on a plethora of previous studies that also point to the 5-HT2CR as an attractive target for the treatment of CUD.

Supplemental Material for Assessing Cocaine Motivational Value: Comparison of Brain Reactivity Bias Toward Cocaine Cues and Cocaine Demand

Supplemental Material for Assessing Cocaine Motivational Value: Comparison of Brain Reactivity Bias Toward Cocaine Cues and Cocaine Demand

Electrophysiological responses to emotional and cocaine cues reveal individual neuroaffective profiles in cocaine users.

Smokers with stronger neuroaffective responses to drug-related cues compared to nondrug-related pleasant images (C > P) are more vulnerable to compulsive smoking than individuals with the opposite brain reactivity profile (P > C). However, it is unknown if these neurobehavioral profiles exist in individuals abusing other drugs. We tested whether individuals with cocaine use disorder (CUD) show similar neuroaffective profiles to smokers. We also monitored eye movements to assess attentional bias toward cues and we further performed exploratory analyses on demographics, personality, and drug use between profiles. Participants with CUD (n = 43) viewed pleasant, unpleasant, cocaine, and neutral images while we recorded electroencephalogram. For each picture category, we computed the amplitude of the late positive potential (LPP), an event-related potential component that reflects motivational relevance. k-means clustering classified participants based on their LPP responses. In line with what has been observed in smokers, clustering participants using LPP responses revealed the presence of two groups: one with larger LPPs to pleasant images compared to cocaine images (P > C) and one group with larger LPPs to cocaine images compared to pleasant images (C > P). Individuals with the C > P reactivity profile also had higher attentional bias toward drug cues. The two groups did not differ on demographic and drug use characteristics, however individuals with the C > P profile reported lower distress tolerance, higher anhedonia, and higher posttraumatic stress symptoms compared to the P > C group. This is the first study to report the presence of these neuroaffective profiles in individuals with CUD, indicating that this pattern may cut across addiction populations. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Sex-dependent effects of chronic stress on punished cocaine self-administration and cue-induced relapse to cocaine seeking

We tested the effects of chronic stress on cocaine relapse after drug-reinforced responding was suppressed by punishment, an animal model of human relapse after self-imposed abstinence due to the negative consequences of drug use. Male rats displayed greater resistance to punishment than females, but daily stress decreased this resistance. Only female rats with a history of chronic stress displayed increased responding for cocaine cues from abstinence Day 1 to Day 8. Thus, the effects of chronic stress on punished cocaine self-administration and cue-induced relapse are dependent on biological sex, and may have implications for more targeted treatments for cocaine addiction.

Sex Differences in Opioid and Psychostimulant Craving and Relapse: A Critical Review.

A widely held dogma in the preclinical addiction field is that females are more vulnerable than males to drug craving and relapse. Here, we first review clinical studies on sex differences in psychostimulant and opioid craving and relapse. Next, we review preclinical studies on sex differences in psychostimulant and opioid reinstatement of drug seeking after extinction of drug self-administration, and incubation of drug craving (time-dependent increase in drug seeking during abstinence). We also discuss ovarian hormones' role in relapse and craving in humans and animal models and speculate on brain mechanisms underlying their role in cocaine craving and relapse in rodent models. Finally, we discuss imaging studies on brain responses to cocaine cues and stress in men and women.The results of the clinical studies reviewed do not appear to support the notion that women are more vulnerable to psychostimulant and opioid craving and relapse. However, this conclusion is tentative because most of the studies reviewed were correlational, not sufficiently powered, and not a priori designed to detect sex differences. Additionally, imaging studies suggest sex differences in brain responses to cocaine cues and stress. The results of the preclinical studies reviewed provide evidence for sex differences in stress-induced reinstatement and incubation of cocaine craving but not cue- or cocaine-induced reinstatement of cocaine seeking. These sex differences are modulated in part by ovarian hormones. In contrast, the available data do not support the notion of sex differences in craving and relapse/reinstatement for methamphetamine or opioids in rodent models. SIGNIFICANCE STATEMENT: This systematic review summarizes clinical and preclinical studies on sex differences in psychostimulant and opioid craving and relapse. Results of the clinical studies reviewed do not appear to support the notion that women are more vulnerable to psychostimulant and opioid craving and relapse. Results of preclinical studies reviewed provide evidence for sex differences in reinstatement and incubation of cocaine seeking but not for reinstatement or incubation of methamphetamine or opioid seeking.

Cocaine cue-induced mesocorticolimbic activation in cocaine users: Effects of personality traits, lifetime drug use, and acute stimulant ingestion.

Stimulant drug-paired cues can acquire the ability to activate mesocorticolimbic pathways and lead to new bouts of drug use. Studies in laboratory animals suggest that these effects are augmented by progressively greater drug use histories, impulsive personality traits, and acute drug ingestion. As a preliminary test of these hypotheses in humans, we exposed cocaine users (n = 14) and healthy volunteers (n = 10) to cocaine-related videos during two functional magnetic resonance imaging (fMRI) sessions, once following acute administration of placebo and once following d-amphetamine (0.3 mg/kg, p.o.). Across sessions, cocaine users showed larger cocaine cue-induced responses than healthy controls in the associative striatum and midbrain. Among the cocaine users, larger drug cue-induced responses during the placebo session were correlated with higher Barratt Impulsiveness Scale (BIS-11) nonplanning scores (associative striatum) and greater lifetime use of stimulant drugs (limbic, associative, and sensorimotor striatum). The administration of d-amphetamine did not augment the cue-induced activations, but, in cocaine users, drug cue-induced striatal activations were more widespread following prolonged cocaine cue exposure. Together, these effects of past and present drug use might aggravate the risk for stimulant drug use problems.

Extinction of Cocaine Memory Depends on a Feed-Forward Inhibition Circuit Within the Medial Prefrontal Cortex

BackgroundCocaine-associated environments (i.e., contexts) evoke persistent memories of cocaine reward and thereby contribute to the maintenance of addictive behavior in cocaine users. From a therapeutic perspective, enhancing inhibitory control over cocaine-conditioned responses is of pivotal importance but requires a more detailed understanding of the neural circuitry that can suppress context-evoked cocaine memories, e.g., through extinction learning. The ventral medial prefrontal cortex (vmPFC) and dorsal medial prefrontal cortex (dmPFC) are thought to bidirectionally regulate responding to cocaine cues through their projections to other brain regions. However, whether these mPFC subregions interact to enable adaptive responding to cocaine-associated contextual stimuli has remained elusive. MethodsWe used antero- and retrograde tracing combined with chemogenetic intervention to examine the role of vmPFC-to-dmPFC projections in extinction of cocaine-induced place preference in mice. In addition, electrophysiological recordings and optogenetics were used to determine whether parvalbumin-expressing inhibitory interneurons and pyramidal neurons in the dmPFC are innervated by vmPFC projections. ResultsWe found that vmPFC-to-dmPFC projecting neurons are activated during unreinforced re-exposure to a cocaine-associated context, and selective suppression of these cells impairs extinction learning. Parvalbumin-expressing inhibitory interneurons in the dmPFC receive stronger monosynaptic excitatory input from vmPFC projections than local dmPFC pyramidal neurons, consequently resulting in disynaptic inhibition of pyramidal neurons. In line with this, we show that chemogenetic suppression of dmPFC parvalbumin-expressing inhibitory interneurons impairs extinction learning. ConclusionsOur data reveal that vmPFC projections mediate extinction of a cocaine-associated contextual memory through recruitment of feed-forward inhibition in the dmPFC, thereby providing a novel neuronal substrate that promotes extinction-induced inhibitory control.

GluN3-Containing NMDA Receptors in the Rat Nucleus Accumbens Core Contribute to Incubation of Cocaine Craving.

Cue-induced cocaine craving progressively intensifies (incubates) after withdrawal from cocaine self-administration in rats and humans. In rats, the expression of incubation ultimately depends on Ca2+-permeable AMPARs that accumulate in synapses onto medium spiny neurons (MSNs) in the NAc core. However, the delay in their accumulation (∼1 month after drug self-administration ceases) suggests earlier waves of plasticity. This prompted us to conduct the first study of NMDAR transmission in NAc core during incubation, focusing on the GluN3 subunit, which confers atypical properties when incorporated into NMDARs, including insensitivity to Mg2+ block and Ca2+ impermeability. Whole-cell patch-clamp recordings were conducted in MSNs of adult male rats 1-68 d after discontinuing extended-access saline or cocaine self-administration. NMDAR transmission was enhanced after 5 d of cocaine withdrawal, and this persisted for at least 68 d of withdrawal. The earliest functional alterations were mediated through increased contributions of GluN2B-containing NMDARs, followed by increased contributions of GluN3-containing NMDARs. As predicted by GluN3-NMDAR incorporation, fewer MSN spines exhibited NMDAR-mediated Ca2+ entry. GluN3A knockdown in NAc core was sufficient to prevent incubation of craving, consistent with biotinylation studies showing increased GluN3A surface expression, although array tomography studies suggested that adaptations involving GluN3B also occur. Collectively, our data show that a complex cascade of NMDAR and AMPAR plasticity occurs in NAc core, potentially through a homeostatic mechanism, leading to persistent increases in cocaine cue reactivity and relapse vulnerability. This is a remarkable example of experience-dependent glutamatergic plasticity evolving over a protracted window in the adult brain.SIGNIFICANCE STATEMENT "Incubation of craving" is an animal model for the persistence of vulnerability to cue-induced relapse after prolonged drug abstinence. Incubation also occurs in human drug users. AMPAR plasticity in medium spiny neurons (MSNs) of the NAc core is critical for incubation of cocaine craving but occurs only after a delay. Here we found that AMPAR plasticity is preceded by NMDAR plasticity that is essential for incubation and involves GluN3, an atypical NMDAR subunit that markedly alters NMDAR transmission. Together with AMPAR plasticity, this represents profound remodeling of excitatory synaptic transmission onto MSNs. Given the importance of MSNs for translating motivation into action, this plasticity may explain, at least in part, the profound shifts in motivated behavior that characterize addiction.

Residual deficits in functional brain activity after chronic cocaine self-administration in rhesus monkeys.

Previous studies in humans and in animals have shown dramatic effects of cocaine on measures of brain function that persist into abstinence. The purpose of this study was to examine the neurobiological consequences of abstinence from cocaine, using a model that removes the potential confound of cocaine cues. Adult male rhesus monkeys self-administered cocaine (0.3 mg/kg/injection; N = 8) during daily sessions or served as food-reinforcement controls (N = 4). Two times per week, monkeys were placed in a neutral environment and presented with a cartoon video for ~30 min, sometimes pre- and sometimes post-operant session, but no reinforcement was presented during the video. After ~100 sessions and when the cocaine groups had self-administered 900 mg/kg cocaine, the final experimental condition was a terminal 2-[14C]-deoxyglucose procedure, which occurred in the neutral (cartoon video) environment; for half of the monkeys in each group, this occurred after 1 day of abstinence and for the others after 30 days of abstinence. Rates of local cerebral glucose metabolism were measured in 57 brain regions. Global rates of cerebral metabolism were significantly lower in animals 1 day and 30 days post-cocaine self-administration when compared to those of food-reinforced controls. Effects were larger in 30- vs. 1-day cocaine abstinence, especially in prefrontal, parietal and cingulate cortex, as well as dorsal striatum and thalamus. Because these measures were obtained from monkeys while in a neutral environment, the deficits in glucose utilization can be attributed to the consequences of cocaine exposure and not to effects of conditioned stimuli associated with cocaine.

Posttraumatic stress symptom clusters differentially predict late positive potential to cocaine imagery cues in trauma-exposed adults with cocaine use disorder

BackgroundWhile studies have investigated the effects of posttraumatic stress disorder (PTSD) symptoms on substance use, information on these associations in the context of drug cue reactivity is lacking, which can provide meaningful information about risk for relapse. The current study assessed the associations between PTSD symptom clusters and reactivity to cues in trauma-exposed adults with cocaine use disorder. MethodsWe recorded electroencephalogram on 52 trauma-exposed participants (Mage = 51.3; SD = 7.0; 15.4 % women) diagnosed with cocaine use disorder while they viewed pleasant (i.e., erotic, romantic, sweet foods), unpleasant (i.e., mutilations, violence, accidents), neutral, and cocaine-related images. Reactivity was measured with the late positive potential (LPP), an indicator of motivational relevance. It was hypothesized that individuals with greater PTSD avoidance and negative alterations in cognition and mood (NACM) symptoms, as determined by the PTSD Checklist for DSM-5 (PCL-5), would have higher LPPs to cocaine-related images, indicating greater cue reactivity. ResultsLinear mixed modeling indicated that higher NACM symptomatology was associated with higher LPPs to cocaine cues and higher arousal/reactivity was associated with lower LPPs to cocaine cues. ConclusionsThese results highlight the potential clinical utility of the LPP in assessing drug cue reactivity in trauma-exposed adults with substance use disorder.

Sustained brain response to repeated drug cues is associated with poor drug-use outcomes.

A threefold increase in fatal cocaine overdoses during the past decade highlights the critical lack of medications for cocaine use disorders. The brain response to drug cues can predict future drug use; however, results have been mixed. We present preliminary evidence that a sustained response to repeated cocaine cues within a single task is a significant predictor of drug-use outcomes. Seventy-three cocaine inpatients were administered a passive-viewing fMRI task, featuring 500ms novel evocative (cocaine, sexual, aversive) and neutral comparator cues in the first half (Half1), which were then repeated in the second half (Half2). After the baseline scan, patients received eight outpatient treatment weeks with twice-weekly drug screens. Drug-use outcome groups were empirically defined based on cocaine-positive or missing urines averaged across the outpatient phase: GOOD (<40%), POOR (>85%), and Intermediate (INT, between 40% and 85%) outcomes. Differences of response to initial (Half1) and repeated (Half2) cues in a priori (cue-reactive) regions were tested between outcome groups (3 [Group]×2 [Halves] ANOVA). An interaction was found in the brain response to drug (but not sex or aversive) cues, with a significant difference between the GOOD and POOR outcome groups in Half2, driven by a significant decrease in brain response by the GOOD outcome group and a sustained brain response by the POOR outcome group, to repeated cocaine cues. The brain response to repeated drug cues may be a useful predictor of future drug use, encouraging future intervention studies to restore a "healthy" (decreasing) response to the repeated presentation of drug cues.