Multimodal frontal neuroimaging markers predict longitudinal craving reduction in abstinent individuals with heroin use disorder.

The variation in improvement among individuals with addiction after abstinence is a critical issue. Here, we aimed to identify robust multimodal markers associated with high response to 8-month abstinence in the individuals with heroin use disorder (HUD) and explore whether the identified markers could be generalized to the individuals with methamphetamine use disorder (MUD). According to the median of craving changes, 53 individuals with HUD with 8-month abstinence were divided into two groups: higher craving reduction and lower craving reduction. At baseline, clinical variables, cortical thickness and subcortical volume, fractional anisotropy (FA) of fibers and resting-state functional connectivity (RSFC) were extracted. Different strategies (single metric, multimodal neuroimaging fusion and multimodal neuroimaging-clinical data fusion) were used to identify reliable features for discriminating the individuals with HUD with higher craving reduction from those with lower reduction. The generalization ability of the identified features was validated in the 21 individuals with MUD. Multimodal neuroimaging-clinical fusion features with best performance was achieved an 87.1 ± 3.89% average accuracy in individuals with HUD, with a moderate accuracy of 66.7% when generalizing to individuals with MUD. The multimodal neuroimaging features, primarily converging in frontal regions (e.g., the left superior frontal (LSF) thickness, FA of the LSF-occipital tract, and RSFC of left middle frontal-right superior temporal lobe), collectively contributed to prediction alongside dosage and attention impulsiveness. In this study, we identified the validated multimodal frontal neuroimaging markers associated with higher response to long-term abstinence and revealed insights for the neural mechanisms of addiction abstinence, contributing to clinical strategies and treatment for addiction.

Predictors of retention in heroin-assisted treatment in Denmark 2010-2018 - A record-linkage study.

INTRODUCTION: While randomized-controlled trials have shown that heroin-assisted treatment (HAT) is superior to methadone maintenance alone in treatment of refractory clients, little is known about client factors associated with retention in HAT in routine care. METHODS: This retrospective cohort study assessed predictors of retention in first treatment episode among a consecutive cohort of clients admitted to HAT in Denmark from 2010 to 2018, who could be matched to the Danish population register and for whom a Short Form Health Survey (SF-36) was available at admission (N = 432). The study derived predictors from client self-reports at intake and administrative data available in national registers. Cox proportional hazards regression modelled retention in treatment. RESULTS: The one-year retention rate was 69.63 % (95 % CI 65.06 %-73.74 %), and the median time in treatment was 2.45 years (95 % CI, 1.83-3.12). Bivariate analyses showed that retention was lower for clients who had recent cocaine or benzodiazepine use and among those who had experienced an overdose in the year prior to enrollment in HAT. Age below 40, recent illegal activity, poorer emotional wellbeing, previous residential treatment experience, and previous intensive outpatient treatment were also predictors of dropout from HAT. CONCLUSIONS: This observational study found that retention in HAT in routine care was similar to rates observed in randomized-controlled trials conducted in other countries. The results suggest that addressing polysubstance use as part of the HAT program may promote long-term retention, as may directing resources to certain subgroups identified at intake, including clients under 40 years and those who report recent criminal activity, emotional problems, or overdoses. The findings that previous residential treatment and intensive outpatient treatment were associated with dropout were unexpected.

Impairment of the GABAergic system in the anterior insular cortex of heroin-addicted males.

Opioid addiction is a global problem, causing the greatest health burden among drug use disorders, with opioid overdose deaths topping the statistics of fatal overdoses. The multifunctional anterior insular cortex (AIC) is involved in inhibitory control, which is severely impaired in opioid addiction. GABAergic interneurons shape the output of the AIC, where abnormalities have been reported in individuals addicted to opioids. In these neurons, glutamate decarboxylase (GAD) with its isoforms GAD 65 and 67 is a key enzyme in the synthesis of GABA, and research data point to a dysregulation of GABAergic activity in the AIC in opioid addiction. Our study, which was performed on paraffin-embedded brains from the Magdeburg Brain Bank, aimed to investigate abnormalities in the GABAergic function of the AIC in opioid addiction by densitometric evaluation of GAD 65/67-immunostained neuropil. The study showed bilaterally increased neuropil density in layers III and V in 13 male heroin-addicted males compared to 12 healthy controls, with significant U-test P values for layer V bilaterally. Analysis of confounding variables showed that age, brain volume and duration of formalin fixation did not confound the results. Our findings suggest a dysregulation of GABAergic activity in the AIC in opioid addiction, which is consistent with experimental data from animal models and human neuroimaging studies.

Fragile Treg cells: Traitors in immune homeostasis?

Regulatory T (Treg) cells play a key role in maintaining immune tolerance and tissue homeostasis. However, in some disease microenvironments, Treg cells exhibit fragility, which manifests as preserved FoxP3 expression accompanied by inflammation and loss of immunosuppression. Fragile Treg cells are formatively, phenotypically and functionally diverse in various diseases, further complicating the role of Treg cells in the immunotherapeutic response and offering novel targets for disease treatment by modulating specific Treg subsets. In this review, we summarize findings on fragile Treg cells to provide a framework for characterizing the formation and role of fragile Treg cells in different diseases, and we discuss how this information may guide the development of more specific Treg-targeted immunotherapies.

Characteristics of Patients Presenting at an Emergency Department for a Heroin Overdose vs Detoxification.

Purpose: This study compares substance use, treatment histories, and sociodemographic characteristics of patients presenting to an emergency department (ED) following a heroin overdose or seeking detoxification services for heroin and examines risk factors for a subsequent return to the ED for a substance-related problem. Methods: A convenience sample of patients presenting for an overdose or detoxification at an urban teaching ED was recruited for this study. During their ED visit, patients were interviewed regarding demographics, substance use experiences, and treatment history. Subsequently, a review of patient records for past and subsequent ED use was performed. Results: Patients requesting detox and those with an overdose were similar in terms of prior treatment. Both groups had similar extensive polysubstance histories. As a group, however, patients presenting for detox were more likely to report use of each of three substances (benzodiazepines, opioid pain medications, and heroin) more than three times per week, compared to those presenting for overdose. Detox patients had higher scores on the 3-item Alcohol Use Disorder Identification Test-C and the drug problems scale compared to overdose patients. Overall, 28% of the patients returned to the ED within 90 days for a drug-related issue, including 8% that returned for an overdose. Factors predictive of a return ED visit included ED visits for substance use in the previous year and recent frequent heroin use. Conclusion: Patients requesting detox were similar in most domains to those presenting following an overdose. Notably, overdose patients were less likely to use heroin more than three times per week compared to detox patients. Both groups were equally likely to return for an SUD reason within 3-months, however for both groups, previous ED visits and recent frequent heroin use predicted a return visit.

Heroin-induced leukoencephalopathy: Chasing the imaging findings.

We present a case of a 29-year-old male who was brought into the hospital due to unresponsiveness and found to have heroin inhalational leukoencephalopathy (HLE). HLE is one component of a broad spectrum of opioid encephalopathies that is associated with heroin inhalation and other opioids. There is considerable overlap of HLE with other toxic and hypoxic-ischemic encephalopathies; however, the specific territories of brain involvement help distinguish it from other cerebral insults. The goal of this study is to help elucidate the findings of HLE and compare these findings to other toxic and hypoxic-ischemic encephalopathies.

Injection Drug Use Alters Plasma Regulation of the B Cell Response.

The opioid epidemic continues to be a major public health issue that includes millions of people who inject drugs (PWID). PWID have increased incidence of serious infections, including HIV as well as metabolic and inflammatory sequelae. We sought to discern the extent of systemic alterations in humoral immunity associated with injection drug use, including alterations in the plasma proteome and its regulation of B cell responsiveness. Comprehensive plasma proteomics analysis of HIV negative/hepatitis C negative individuals with a history of recent injection heroin use was performed using mass spectrometry and ELISA. The effects of plasma from PWID and healthy controls on the in vitro proliferation and transcriptional profile of B cell responses to stimulation were determined by flow cytometry and RNA-Seq. The plasma proteome of PWID was distinct from healthy control individuals, with numerous immune-related analytes significantly altered in PWID, including complement (C3, C5, C9), immunoglobulin (IgD, IgM, kappa light chain), and other inflammatory mediators (CXCL4, LPS binding protein, C-reactive protein). The plasma of PWID suppressed the in vitro proliferation of B cells. Transcriptome analysis indicated that PWID plasma treatment increased B cell receptor and CD40 signaling and shifted B cell differentiation from plasma cell-like toward germinal center B cell-like transcriptional profiles. These results indicate that the systemic inflammatory milieu is substantially altered in PWID and may impact their B cell responses.

Opioid-related xylazine toxicity manifesting as myonecrosis, rhabdomyolysis, multifocal ischemic cerebral infarcts, and cerebral edema.

This article provides a report of a case of organ dysfunction, myonecrosis, rhabdomyolysis, multifocal ischemic cerebral infarcts, and cerebral edema after a patient's use of xylazine and fentanyl. Within the US opioid epidemic, xylazine is emerging as a troubling national sub-story. The prevalence of xylazine within illicitly manufactured opioids and the proportion of opioid-involved overdose deaths with detected xylazine are rising dramatically, the latter increasing 276% between 2019 and 2022. A 27-year-old woman with opioid use disorder, active intravenous drug use, and prior bacteremia presented to our institution's emergency department (ED) with left lower extremity pain and associated weakness, new acute bilateral hearing loss, multiple electrolyte derangements, and cerebral infarcts followed by cerebral edema, leading to an emergent sub-occipital decompressive craniectomy and placement of an external ventricular drain. A definitive mechanism was not determined; however, we hypothesized that xylazine toxicity played a role in her clinical presentation, which could have future clinical implications, including the possibility to incorporate xylazine as part of toxicology screens.

Psilocybin reduces heroin seeking behavior and modulates inflammatory gene expression in the nucleus accumbens and prefrontal cortex of male rats.

Preclinical and human studies indicate psilocybin may reduce perseverant maladaptive behaviors, including nicotine and alcohol seeking. Such studies in the opioid field are lacking, though opioids are involved in more >50% of overdose deaths. Psilocybin is an agonist at the serotonin 2A receptor (5-HT2AR), a well-documented target for modulation of drug seeking, and evidence suggests 5-HT2AR agonists may dampen motivation for opioids. We sought to investigate the therapeutic efficacy of psilocybin in mediating cessation of opioid use and maintenance of long-lasting abstinence from opioid seeking behavior in a rat model of heroin self-administration (SA). Psilocybin or 5-HT2AR antagonists ketanserin and volinanserin were administered systemically to rats prior to SA of 0.075 mg/kg/infusion of heroin, or relapse following forced abstinence. Psilocybin did not alter heroin taking, but a single exposure to 3.0 mg/kg psilocybin 4-24 hours prior to a relapse test blunted cue-induced heroin seeking. Conversely, 5-HT2AR antagonists exacerbated heroin relapse. To begin to elucidate mechanisms of psilocybin, drug-naïve rats received psilocybin and/or ketanserin, and tissue was collected from the prefrontal cortex (PFC), a region critical for drug seeking and responsive to psilocybin, 24 hours later for RNA-sequencing. 3.0 mg/kg psilocybin regulated ~2-fold more genes in the PFC than 1.0 mg/kg, including genes involved in the cytoskeleton and cytokine signaling. Ketanserin blocked >90% of psilocybin-regulated genes, including the IL-17a cytokine receptor, Il17ra. Psychedelic compounds have reported anti-inflammatory properties, and therefore we performed a gene expression array to measure chemokine/cytokine molecules in the PFC of animals that displayed psilocybin-mediated inhibition of heroin seeking. Psilocybin regulated 4 genes, including Il17a, and a subset of genes correlated with relapse behavior. Selective inhibition of PFC IL-17a was sufficient to reduce heroin relapse. We conclude that psilocybin reduces heroin relapse and highlight IL-17a signaling as a potential downstream pathway of psilocybin that also reduces heroin seeking.

Heroin Overdose Complicated by Compartment Syndrome, Rhabdomyolysis, and Acute Renal Failure.

The opioid-abuse epidemic is a problem that continues to persist world-wide. As such, appropriately evaluating and treating such patients is crucial, especially when considering the various complications that may arise. In rare cases, opioid overdoses can be complicated by compartment syndrome, rhabdomyolysis, and acute renal failure. All three of these complications can result in life threatening emergencies. We present a case of a 38-year-old male who was brought to the emergency department after reportedly being found lying on the ground for an unknown period of time from suspected heroin overdose. He was initially treated with 2 milligrams (mg) of intramuscular naloxone en route via emergency medical services with appropriate response. Shortly after arrival to the emergency department, the patient complained of severe right lower extremity pain, paresthesia and paralysis. Patient developed acute lower extremity compartment syndrome that was further complicated by rhabdomyolysis and acute renal failure. While emergency medicine physicians are familiar with the common complications of heroin overdose including mental status changes, respiratory depression and gastrointestinal symptoms, they must also be familiar with the less common ones. Notably, acute compartment syndrome. Compartment syndrome is ultimately a clinical diagnosis and warrants emergent surgical consultation. Every patient presenting to the emergency department warrants a complete, thorough physical examination to evaluate for any and all life-threatening conditions, regardless of the presenting complaint.

Novel psychoplastogen DM506 reduces cue-induced heroin-seeking and inhibits tonic GABA currents in the Prelimbic Cortex.

Opioid use disorder is a major public health crisis that is manifested by persistent drug-seeking behavior and high relapse frequency. Most of the available treatments rely on targeting opioid receptors using small molecules that do not provide sustained symptom alleviation. Psychoplastogens are a novel class of non-opioid drugs that produce rapid and sustained effects on neuronal plasticity, intended to produce therapeutic benefits. Ibogalogs are synthetic derivatives of iboga alkaloids that lack hallucinogenic or adverse side effects. In the current study, we examine the therapeutic potential of DM506, a novel ibogalog lacking any cardiotoxic or hallucinogenic effects, in cue-induced seeking behavior following heroin self-administration. At a single systemic dose of 40 mg/kg, DM506 significantly decreased cue-induced seeking in both male and female rats at abstinence day 1 (AD1) following heroin self-administration. Upon re-testing for cue-induced seeking at AD14, we found that males receiving DM506 continued to show decreased cue-induced seeking, an effect not observed in females. Since there is evidence of psychedelics influencing tonic GABA currents, and opioid and psychoplastogen-mediated neuroadaptations in the medial prefrontal cortex (PrL) underlying its functional effects, we performed patch-clamp recordings on PrL slices of drug-naïve rats with an acute application or chronic incubation with DM506. Tonic GABA current was decreased in slices incubated with DM506 for 2 h. qPCR analysis did not reveal any differences in the mRNA levels of GABAA receptor α and δ subunits at AD14 in heroin and saline self-administered animals that received vehicle or DM506 at AD1. Overall, our data indicate that DM506 attenuates cue-induced heroin seeking and inhibits tonic GABA current in the prelimbic cortex.

Bedside urine testing for fentanyl in self-reported heroin users in a tertiary Brisbane emergency department.

OBJECTIVE: To determine if patients presenting to our toxicology unit following self-reported heroin use had positive urine immunoassay testing for fentanyl or its analogues. METHODS: Urine samples from consenting patients were tested at the bedside for the presence of opiates or fentanyl and its analogues. RESULTS: Over a 30-month period, 58 patients were recruited. All samples tested positive for opiates, but none tested positive for fentanyl or its analogues. CONCLUSION: In patients presenting to our toxicology unit in Brisbane, we did not find any cases where the urine of patients self-reporting heroin exposure tested positive for fentanyl or its analogues.

Suicidal thoughts and behaviors among untreated illicit substance users: a population-based study.

OBJECTIVES: Research regarding the contribution of specific psychoactive substances to suicidality has yielded equivocal results. The present study examined the prevalence and factors associated with suicidal thoughts and behaviors among a population-based sample of untreated illicit substance users. METHODS: A total of 616 illicit substance users who were recruited from high-risk areas of Shiraz using snowball sampling participated in the study. Eligible participants were individuals aged 18 years and older who regularly used one illicit psychoactive substance (e.g., opioids, heroin, cannabinoids, stimulants, hallucinogens) for at least one year and who had received no treatment for their drug use during the past year. Data were collected regarding socio-demographic characteristics, mental history, and substance use habits. Data regarding suicidal thoughts and behaviors were assessed using the Beck Suicidal Ideation Scale (BSIS) and self-reports of previous suicide attempts. Multiple logistic regression analysis was used to identify independent variables associated with suicidality. RESULTS: Among the participants, 23.6% reported having had suicidal thoughts during the past week and 6.7% reported having attempted suicide during the past year. Methamphetamine was reported as the primary substance of use among approximately half of the participants who attempted suicide during past year (49.2%). Multiple logistic regression analysis showed that current suicidal thoughts were independently associated with having no job, a history of mental health condition, previous suicidal attempts, concurrent use of more than one substance, and using methamphetamine and heroin as the primary substances. Suicidal thoughts were not associated with increased odds of regular opium and cannabis use. CONCLUSION: Both methamphetamine and heroin use are significantly associated with current suicidal thoughts. Evaluation of the risk of suicidality by physicians and mental health care professionals in both community and outpatient settings would be especially appropriate among those individuals using these psychoactive substances.

Identification of N-pyrrolidino protonitazene in powders sold as heroin and associated with overdose clusters in Dublin and Cork, Ireland.

Synthetic opioids have been associated globally with adverse effects in drug users. The nitazene group of drugs is a relatively new addition to the synthetic opioid class emerging in Europe in 2019. Some nitazenes have been shown to be more potent than fentanyl. Overdose clusters in heroin users in Dublin (57 cases) and Cork (20 cases), Ireland, in November and December 2023, respectively, prompted a rapid response from a number of Irish laboratories to identify the substance(s) of concern. Light brown (tan) powders were obtained from cases associated with overdoses, and the results from these analyses by collaboration of four laboratories are reported here. The samples were found to contain N-pyrrolidino protonitazene (protonitazepyne), caffeine, paracetamol, benzoic acid and mannitol.

Changes in injecting versus smoking heroin, fentanyl, and methamphetamine among people who inject drugs in San Diego, California, 2020-2023.

BACKGROUND: Amidst an increasingly toxic drug supply in North America, people who inject drugs may be transitioning to smoking them. We aimed to assess changes in injecting and smoking opioids and methamphetamine among a cohort of people who inject drugs from San Diego, California. METHODS: Over five six-month periods spanning October 2020-April 2023, we assessed prevalence of injecting and smoking opioids or methamphetamine and whether participants used these drugs more frequently by smoking than injecting. Multivariable Poisson regression via generalized estimating equations was used to examine time trends. RESULTS: Of 362 participants, median age was 40 years; a minority were female (29%), Hispanic/Latinx/Mexican (45%), and housed (33%). Among this cohort, of whom 100% injected (and 84% injected and smoked) in period one (October 2020-April 2021), by period five (November 2022-April 2023), 34% only smoked, 59% injected and smoked, and 7% only injected. By period five, the adjusted relative risk (aRR) of injecting opioids was 0.41 (95% Confidence Interval [CI]: 0.33, 0.51) and the aRR for injecting methamphetamine was 0.50 (95% CI: 0.39, 0.63) compared to period one. Risks for smoking fentanyl rose significantly during period three (aRR=1.44, 95% CI: 1.06, 1.94), four (aRR=1.65, 95% CI: 1.24, 2.20) and five (aRR=1.90, 95% CI: 1.43, 2.53) compared to period one. Risks for smoking heroin and methamphetamine more frequently than injecting these drugs increased across all periods. CONCLUSIONS: Opioid and methamphetamine injection declined precipitously, with notable increases in smoking these drugs. Research is needed to understand the health consequences of these trends.

Pharmacologic profile of ITI-333: a novel molecule for treatment of substance use disorders.

RATIONALE: Medications are urgently needed to treat symptoms of drug withdrawal and mitigate dysphoria and psychiatric comorbidities that drive opioid abuse and relapse. ITI-333 is a novel molecule in development for treatment of substance use disorders, psychiatric comorbidities, and pain. OBJECTIVE: Characterize the preclinical profile of ITI-333 using pharmacological, behavioral, and physiological assays. METHODS: Cell-based assays were used to measure receptor binding and intrinsic efficacy of ITI-333; animal models were employed to assess effects on opioid reinstatement, precipitated oxycodone withdrawal, and drug abuse liability. RESULTS: In vitro, ITI-333 is a potent 5-HT2A receptor antagonist (Ki = 8 nM) and a biased, partial agonist at µ-opioid (MOP) receptors (Ki = 11 nM; lacking ß-arrestin agonism) with lesser antagonist activity at adrenergic α1A (Ki = 28 nM) and dopamine D1 (Ki = 50 nM) receptors. In vivo, ITI-333 blocks 5-HT2A receptor-mediated head twitch and MOP receptor-mediated effects on motor hyperactivity in mice. ITI-333 alone is a naloxone-sensitive analgesic (mice) which suppresses somatic signs of naloxone-precipitated oxycodone withdrawal (mice) and heroin cue-induced reinstatement responding without apparent tolerance or physical dependence after chronic dosing (rats). ITI-333 did not acutely impair gastrointestinal or pulmonary function (rats) and was not intravenously self-administered by heroin-maintained rats or rhesus monkeys. CONCLUSIONS: ITI-333 acts as a potent 5-HT2A receptor antagonist, as well a biased MOP receptor partial agonist with low intrinsic efficacy. ITI-333 mitigates opioid withdrawal/reinstatement, supporting its potential utility as a treatment for OUD.

Patterns of drug use among people who inject drugs: A global systematic review and meta-analysis.

BACKGROUND: A better understanding of global patterns of drug use among people who inject drugs can inform interventions to reduce harms related to different use profiles. This review aimed to comprehensively present the geographical variation in drug consumption patterns among this population. METHODS: Systematic searches of peer reviewed (PsycINFO, Medline, Embase) and grey literature published from 2008-2022 were conducted. Data on recent (past year) and lifetime drug use among people who inject drugs were included. Data were extracted on use of heroin, amphetamines, cocaine, benzodiazepines, cannabis, alcohol, and tobacco; where possible, estimates were disaggregated by route of administration (injecting, non-injecting, smoking). National estimates were generated and, where possible, regional, and global estimates were derived through meta-analysis. RESULTS: Of 40,427 studies screened, 394 were included from 81 countries. Globally, an estimated 78.1 % (95 %CI:70.2-84.2) and 71.8 % (65.7-77.2) of people who inject drugs had recently used (via any route) and injected heroin, while an estimated 52.8 % (47.0-59.0) and 19.8 % (13.8-26.5) had recently used and injected amphetamines, respectively. Over 90 % reported recent tobacco use (93.5 % [90.8-95.3]) and recent alcohol use was 59.1 % (52.6-65.6). In Australasia recent heroin use was lowest (49.4 % [46.8-52.1]) while recent amphetamine injecting (64.0 % [60.8-67.1]) and recent use of cannabis (72.3 % [69.9-74.6]) were higher than in all other regions. Recent heroin use (86.1 % [78.3-91.4]) and non-injecting amphetamine use (43.3 % [38.4-48.3]) were highest in East and Southeast Asia. Recent amphetamine use (75.8 % [72.7-78.8]) and injecting heroin use (84.8 % (81.4-87.8) were highest in North America while non-injecting heroin use was highest in Western Europe (45.0 % [41.3-48.7]). CONCLUSION: There is considerable variation in types of drugs and routes of administration used among people who inject drugs. This variation needs to be considered in national and global treatment and harm reduction interventions to target the specific behaviours and harms associated with these regional profiles of use.

Pan-striatal reduction in the expression of the astrocytic dopamine transporter precedes the development of dorsolateral striatum dopamine-dependent incentive heroin seeking habits.

The emergence of compulsive drug-seeking habits, a hallmark feature of substance use disorder, has been shown to be predicated on the engagement of dorsolateral striatal control over behaviour. This process involves the dopamine-dependent functional coupling of the anterior dorsolateral striatum (aDLS) with the nucleus accumbens core, but the mechanisms by which this coupling occurs have not been fully elucidated. The striatum is tiled by a syncytium of astrocytes that express the dopamine transporter (DAT), the level of which is altered in individuals with heroin use disorder. Astrocytes are therefore uniquely placed functionally to bridge dopamine-dependent mechanisms across the striatum. Here we tested the hypothesis that exposure to heroin influences the expression of DAT in striatal astrocytes across the striatum before the development of DLS-dependent incentive heroin seeking habits. Using Western-blot, qPCR, and RNAscope™, we measured DAT protein and mRNA levels in whole tissue, culture and in situ astrocytes from striatal territories of rats with a well-established cue-controlled heroin seeking habit and rats trained to respond for heroin or food under continuous reinforcement. Incentive heroin seeking habits were associated with a reduction in DAT protein levels in the anterior aDLS that was preceded by a heroin-induced reduction in DAT mRNA and protein in astrocytes across the striatum. Striatal astrocytes were also shown to be susceptible to direct dopamine- and opioid-induced downregulation of DAT expression. These results suggest that astrocytes may critically regulate the striatal dopaminergic adaptations that lead to the development of incentive heroin seeking habits.

Interfering with reconsolidation by rimonabant results in blockade of heroin-associated memory.

Drug-associated pathological memory remains a critical factor contributing to the persistence of substance use disorder. Pharmacological amnestic manipulation to interfere with drug memory reconsolidation has shown promise for the prevention of relapse. In a rat heroin self-administration model, we examined the impact of rimonabant, a selective cannabinoid receptor indirect agonist, on the reconsolidation process of heroin-associated memory. The study showed that immediately administering rimonabant after conditioned stimuli (CS) exposure reduced the cue- and herion + cue-induced heroin-seeking behavior. The inhibitory effects lasted for a minimum of 28 days. The effect of Rimonabant on reduced drug-seeking was not shown when treated without CS exposure or 6 hours after CS exposure. These results demonstrate a disruptive role of rimonabant on the reconsolidation of heroin-associated memory and the therapeutic potential in relapse control concerning substance use disorder.