Inverse pattern of GABAergic system impairment in the external versus internal globus pallidus in male heroin addicts.

Opioid addiction is a global problem that has been exacerbated in the USA and Europe by the COVID-19 pandemic. The globus pallidus (GP) plays a prominent neurobiological role in the regulation of behaviour as an output station of the striato-pallidal system. GABAergic large projection neurons are the main neuronal type in the external (EGP) and internal (IGP) parts of the GP, where addiction-specific molecular and functional abnormalities occur. In these neurons, glutamate decarboxylase (GAD) with isoforms GAD 65 and 67 is a key enzyme in GABA synthesis, and experimental studies suggest GAD dysregulation in the GP of heroin addicts. Our study, which was performed on paraffin-embedded brains from the Magdeburg Brain Bank, aimed to investigate abnormalities in the GABAergic function of large GP neurons by densitometric evaluation of their GAD 65/67-immunostained thick dendrites. The study revealed a bilaterally decreased fibres density in the EGP paralleled by the increase in the IGP in 11 male heroin addicts versus 11 healthy controls (significant U-test P values). The analysis of confounding variables found no interference of age, brain volume, and duration of formalin fixation with the results. Our findings suggest a dysregulation of GABAergic activity in the GP of heroin addicts, which is consistent with experimental data from animal models and plays potentially a role in the disturbed function of basal ganglia circuit in opioid addiction.

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.

Glutamatergic neurons in ventral pallidum modulate heroin addiction via epithalamic innervation in rats.

Glutamatergic neurons in ventral pallidum (VPGlu) were recently reported to mediate motivational and emotional behavior, but its role in opioid addiction still remains to be elucidated. In this study we investigated the function of VPGlu in the context-dependent heroin taking and seeking behavior in male rats under the ABA renewal paradigm. By use of cell-type-specific fiber photometry, we showed that the calcium activity of VPGlu were inhibited during heroin self-administration and context-induced relapse, but activated after extinction in a new context. The drug seeking behavior was accompanied by the decreased calcium signal of VPGlu. Chemogenetic manipulation of VPGlu bidirectionally regulated heroin taking and seeking behavior. Anterograde tracing showed that the lateral habenula, one of the epithalamic structures, was the major output region of VPGlu, and its neuronal activity was consistent with VPGlu in different phases of heroin addiction and contributed to the motivation for heroin. VPGlu axon terminals in LHb exhibited dynamic activity in different phases of heroin addiction. Activation of VPGlu-LHb circuit reduced heroin seeking behavior during context-induced relapse. Furthermore, the balance of excitation/inhibition from VP to LHb was shifted to enhanced glutamate transmission after extinction of heroin seeking motivation. Overall, the present study demonstrated that the activity of VPGlu was involved in the regulation of heroin addiction and identified the VPGlu-LHb pathway as a potential intervention to reduce heroin seeking motivation.

[Challenges in the treatment of opioid dependence]. / Aktuelle Herausforderungen in der Behandlung der Opioidabhängigkeit.

BACKGROUND: The number of persons using opioids has increased worldwide in the last decade, particularly the use of opioid analgesics in North America and Africa. In Germany, the prevalence of heroin addiction has remained relatively stable. METHOD: Narrative review of the literature. RESULTS: Opioid-assisted maintenance treatment (OMT) with the established substances methadone, levomethadone, slow-release morphine and buprenorphine is recommended as the first-line treatment for heroin dependence. The OMT reduces the use of heroin, mortality and individual suffering and improves the quality of life and physical health. A diamorphine and heroine-assisted treatment is an option for people who do not benefit from conventional OMT. An alternative to the use of diamorphine could be treatment with hydromorphone hydrochloride. The regulations on carrying out maintenance treatment in the Controlled Substances Prescription Act and the guidelines of the Federal Medical Association in Germany have been loosened based on the experiences of the COVID-19 pandemic, for example with respect to take-home prescriptions. There is an ongoing intensive discussion on how to deal with the decreasing number of outpatient clinics offering OMT. CONCLUSION: The first-line treatment for opioid addiction is opioid-assisted substitution treatment, including diamorphine and heroin-assisted treatment. Long-acting depot medications and implants still play a subordinate role.

Metabolic and functional substrates of impulsive decision-making in individuals with heroin addiction after prolonged methadone maintenance treatment.

Elevated impulsivity has been frequently reported in individuals with opioid addiction receiving methadone maintenance therapy (MMT), but the underlying neural mechanisms and cognitive subprocesses are not fully understood. We acquired functional magnetic resonance imaging (fMRI) data from 37 subjects with heroin addiction receiving long-term MMT and 33 healthy controls who performed a probabilistic reversal learning task, and measured their resting-state brain glucose using fluorine-18-fluorodeoxyglucose positron emission tomography (18F-FDG PET). Subjects receiving MMT exhibited significantly elevated self-reported impulsivity, and computational modeling revealed a marked impulsive decision bias manifested as switching more frequently without available evidence. Moreover, this impulsive decision bias was associated with the dose and duration of methadone use, irrelevant to the duration of heroin use. During the task, the switch-related hypoactivation in the left rostral middle frontal gyrus was correlated with the impulsive decision bias while the function of reward sensitivity was intact in subjects receiving MMT. Using prior brain-wide receptor density data, we found that the highest variance of regional metabolic abnormalities was explained by the spatial distribution of µ-opioid receptors among 10 types of neurotransmitter receptors. Heightened impulsivity in individuals receiving prolonged MMT is manifested as atypical choice bias and noise in decision-making processes, which is further driven by deficits in top-down cognitive control, other than reward sensitivity. Our findings uncover multifaceted mechanisms underlying elevated impulsivity in subjects receiving MMT, which might provide insights for developing complementary therapies to improve retention during MMT.

Ribosomal DNA transcription is increased in the left nucleus accumbens of heroin-dependent males.

Opioid addiction is a worldwide problem accentuated in the USA and European countries by the COVID-19 pandemic. The nucleus accumbens (NAc) plays an outstanding neurobiological role in opioid addiction as a part of the striatum and key component of brain reward system. The striatal GABAergic medium spiny projection neurons (MSNs) are the main neuronal type in the NAc where addiction-specific synaptic plasticity occurs. The activity of ribosomal DNA (rDNA) transcription is crucial for neural plasticity and molecular studies suggest its increase in the NAc of heroin addicts. Silver-stained argyrophilic nucleolar organizer region (AgNOR) areas visualised in neuronal nuclei in paraffin-embedded brain sections are reliable morphological estimators of rDNA transcription and thus surrogate markers for the activity of brain regions. Our study revealed increased AgNOR areas in MSNs of the left NAc in 11 heroin addicts versus 11 healthy controls from the Magdeburg Brain Bank (U-test P = 0.007). No differences were observed in another investigated part of the striatum, namely the head of caudate nucleus, which is located closely to the NAc. The results were not confounded by significant differences in the age, brain volume and time of formalin fixation existing between compared groups. Our findings suggest an increased NAc activity in heroin addicts, which is consistent with human and animal experimental data.

Assessing effect of long-term abstinence on coupling of three core brain networks in male heroin addicts: A resting-state functional magnetic resonance imaging study.

Abstinence is one of the important measures for heroin addiction. However, it is unknown whether long-term abstinence (LA) would improve the coupling among three core brain networks (salience, default mode, and executive control) and decrease craving in treated heroin addicts. Forty-three heroin addicts with LA, 27 heroin addicts with short-term abstinence (SA), and 46 demographically matched healthy controls (HC) participated in the resting-state functional magnetic resonance imaging study. The authors compared the functional connectivity among the three groups and examined how the coupling among salience, default mode, and executive control networks related to duration of abstinence and craving before and after drug cue exposure among heroin addicts. Compared with the SA group, with a tendency toward the HC group, the LA group showed lower drug cue-induced craving, stronger connectivity between the dorsal anterior cingulate cortex (a key node of salience network) and left dorsolateral prefrontal cortex and right posterior parietal cortex (key nodes of executive control network), and stronger connectivity between the right dorsolateral prefrontal cortex and precuneus (a key node of default mode network). Meanwhile, the right dorsolateral prefrontal cortex-precuneus connectivity positively correlated with duration of abstinence. The LA and SA groups demonstrated lower connectivity between the left anterior insula (a key node of salience network) and dorsolateral prefrontal cortex and lower connectivity within the left dorsolateral prefrontal cortex, compared with the HC group. Our findings revealed that LA is associated with lower drug cue induced craving and improve the coupling among the three core brain networks in heroin addicts.

Increased expression of plasma hsa-miR-181a in male patients with heroin addiction use disorder.

BACKGROUND: Drug addiction is an uncontrolled, chronic, and recurrent encephalopathy that presently lacks specific and characteristic biomarkers for diagnosis and treatment. As regulators of gene expression, microRNAs (miRNAs) are increasingly used for diagnostic and prognostic purposes in various disease states. Previous studies indicated that miRNAs play important roles in the development and progression of drug addictions, including addiction to methamphetamine, cocaine, alcohol, and heroin. METHODS: We identified significant miRNAs using the microarray method and then validated the hsa-miR-181a expression levels in 53 heroin addiction patients and 49 normal controls using quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). Finally, the potential associations between transcriptional levels in heroin addiction patients and their clinicopathological features were analyzed. RESULTS: A total of 2006 miRNAs were differentially expressed between heroin addiction patients and normal controls. The top 10 up-regulated miRNAs in patients were hsa-miR-21a, hsa-miR-181a, hsa-miR-4459, hsa-miR-4430, hsa-miR-4306, hsa-miR-22-3P, hsa-miR-486-5P, hsa-miR-371b-5P, hsa-miR-92a-3P, and hsa-miR-5001-5P. The top 10 down-regulated miRNAs in patients were hsa-miR-3195, hsa-miR-4767, hsa-miR-3135b, hsa-miR-6087, hsa-miR-1181, hsa-miR-4785, hsa-miR-718, hsa-miR-3141, hsa-miR-652-5P, and hsa-miR-6126. The expression level of hsa-miR-181a in heroin addiction patients was significantly increased compared with that in normal controls (P < .001). The area under the receiver operating characteristic curve of hsa-miR-181a was 0.783, the sensitivity was 0.867, and the specificity was 0.551. CONCLUSIONS: The increased expression of hsa-miR-181a in the plasma of heroin patients may be a consequence of the pathological process of heroin abuse. This study highlights the potential of hsa-miR-181a as a novel biomarker for the diagnosis of heroin addiction.

Cognitive enhancers as a treatment for heroin relapse and addiction.

Heroin addiction is a disorder that stems from maladaptive plasticity within neural circuits and produces broad cognitive deficits. Despite considerable advances in psychotherapy and pharmacotherapy for heroin relapse and addiction, effective treatments for heroin use disorder are still lacking. Increasing preclinical evidence indicates that heroin seeking behavior is persistent after withdrawal, while cognitive dysfunctions associated with chronic heroin use are an important contributing factor to risk of heroin relapse and addiction. Cognitive enhancers may be used to stimulate treatment success and enhance treatment efficacy. The purpose of this review is to outline the literature that demonstrates the cognitive deficits during the development of heroin addiction and withdrawal process, and several factors that underline the efficacy of cognitive enhancers for heroin use disorders. The review, then, examines the potential use and pharmacological mechanisms of cognitive enhancers that act on cholinergic, glutamatergic, dopaminergic or adrenergic pathways. It also examines the effects of compounds that alter CREB signaling and epigenetic mechanisms in animal model of heroin relapse. The current body of research reveals the new insights into the pharmacological mechanisms underlying heroin addiction and holds a significant promise for cognitive enhancers as an improved approach to treat heroin use disorder in a more efficient and persistent way.

Cost-Effectiveness of Take-Home Naloxone for the Prevention of Overdose Fatalities among Heroin Users in the United Kingdom.

BACKGROUND: Heroin overdose is a major cause of premature death. Naloxone is an opioid antagonist that is effective for the reversal of heroin overdose in emergency situations and can be used by nonmedical responders. OBJECTIVE: Our aim was to assess the cost-effectiveness of distributing naloxone to adults at risk of heroin overdose for use by nonmedical responders compared with no naloxone distribution in a European healthcare setting (United Kingdom). METHODS: A Markov model with an integrated decision tree was developed based on an existing model, using UK data where available. We evaluated an intramuscular naloxone distribution reaching 30% of heroin users. Costs and effects were evaluated over a lifetime and discounted at 3.5%. The results were assessed using deterministic and probabilistic sensitivity analyses. RESULTS: The model estimated that distribution of intramuscular naloxone, would decrease overdose deaths by around 6.6%. In a population of 200,000 heroin users this equates to the prevention of 2,500 premature deaths at an incremental cost per quality-adjusted life year (QALY) gained of £899. The sensitivity analyses confirmed the robustness of the results. CONCLUSIONS: Our evaluation suggests that the distribution of take-home naloxone decreased overdose deaths by around 6.6% and was cost-effective with an incremental cost per QALY gained well below a £20,000 willingness-to-pay threshold set by UK decision-makers. The model code has been made available to aid future research. Further study is warranted on the impact of different formulations of naloxone on cost-effectiveness and the impact take-home naloxone has on the wider society.

Pharmacotherapy for opioid addiction in community corrections.

Pharmacotherapy for opioid addiction with methadone, buprenorphine, and naltrexone has proven efficacy in reducing illicit opioid use. These treatments are under-utilized among opioid-addicted individuals on parole, probation, or in drug courts. This paper examines the peer-reviewed literature on the effectiveness of pharmacotherapy for opioid addiction of adults under community-based criminal justice supervision in the US. Compared to general populations, there are relatively few papers addressing the separate impact of pharmacotherapy on individuals under community supervision. Tentative conclusions can be drawn from the extant literature. Reasonable evidence exists that illicit opioid use and self-reported criminal behaviour decline after treatment entry, and that these outcomes are as favourable among individuals under criminal justice supervision as the general treatment population. Surprisingly, there is no conclusive evidence regarding the extent to which pharmacotherapy impacts the likelihood of arrest and incarceration among individuals under supervision. However, given the proven efficacy of these three medications in reducing illicit opioid use and the evidence that, in the general population, methadone and buprenorphine treatment are associated with reduction in overdose mortality, the use of all three pharmacotherapies among patients under criminal justice supervision should be expanded while more data are collected on their impact on arrest and incarceration.

Psychopathology of addiction: Can the SCL90-based five-dimensional structure differentiate Heroin Use Disorder from a non-substance-related addictive disorder such as Gambling Disorder?

BACKGROUND: In the Gambling Disorder (GD), there is no exogenous drug administration that acts as the central core of the traditional meaning of addiction. A specific psychopathology of Substance Use Disorders has been proposed recently. In a sample of Heroin Use Disorder (HUD) patients entering opioid agonist treatment, it became possible to identify a group of 5 mutually exclusive psychiatric dimensions: Worthlessness-Being trapped (W-BT), Somatic Symptoms (SS), Sensitivity-Psychoticism (SP), Panic Anxiety (PA) and Violence-Suicide (VS). The specificity of these dimensions was suggested by the absence of their correlations with treatment choice, active substance use, psychiatric comorbidity and the principal substance of abuse and by the opportunity, through their use, of fully discriminating HUD from Major Depression patients and, partially, from obese non-psychiatric patients. To further support this specificity in the present study, we tested the feasibility of discriminating HUD patients from those affected by a non-substance-related addictive behaviour, such as GD. In this way, we also investigated the psychopathological peculiarities of GD patients. METHODS: We compared the severity and frequency of each of the five aspects found by us, in 972 (83.5% males; mean age 30.12 ± 6.6) HUD and 110 (50% males; average age 30.12 ± 6.6) GD patients at univariate (T test; Chi square) and multivariate (discriminant analysis and logistic regression) level. RESULTS: HUD patients showed higher general psychopathology indexes than GD patients. The severity of all five psychopathological dimensions was significantly greater in HUD patients. Discriminant analysis revealed that SS and VS severity were able to discriminate between HUD (higher severity) and GD patients (lower severity), whereas PA and SP could not. W-BT severity was negatively correlated with SS and VS; GD patients were distinguished by low scores for SS and VS low scores associated with high ones for W-BT. Psychopathological subtypes characterized by SS and VS symptomatology were better represented in HUD patients, whereas PA symptomatology was more frequent in GD individuals. No differences were observed regarding the W-BT and SP dimensions. At multivariate level, the one prominent characteristic of HUD patients was the presence of SS (OR = 5.43) as a prominent qualification for psychopathological status. CONCLUSIONS: Apart from the lower severity of all psychopathological dimensions, only the lower frequency of SS typology seems to be the prominent factor in GD patients. The SCL90-defined structure of opioid addiction seems to be useful even in non-substance-related addictive disorders, as in the case of GD patients, further supporting the possible existence of a psychopathology specific to addiction.

Investigation of brain electrophysiological properties among heroin addicts: Quantitative EEG and event-related potentials.

This study aims to introduce a new approach of a comprehensive paradigm to evaluate brain electrophysiological properties among addicts. Electroencephalographic spectral power as well as amplitudes and latencies of mismatch negativity (MMN), P300, and P600 components were evaluated among 19 male heroin addicts and 19 healthy nonsmoker subjects using a paradigm consisting of three subparadigms, namely (1) digit span Wechsler test, (2) auditory oddball, and (3) visual cue-reactivity oddball paradigms. Task 1 provided auditory P300 and P600 in association with working memory. Task 2 provided auditory P300 as well as small and large deviant MMN event-related potential (ERPs). Finally, task 3 provided visual cue-reactivity P300. Results show that beta power was higher among heroin addicts while delta, theta, and alpha powers were decreased compared with healthy subjects. ERP analysis confirmed the decline of brain-evoked potential amplitudes when compared with healthy subjects, thus indicating a broad neurobiological vulnerability of preattentive and attentional processing including attentional deficits and compromise of discrimination abilities. The prolonged latency of ERPs reflects poor cognitive capacity in the engagement of attention and memory resources. On the other hand, an increase of attention towards the heroin-related stimuli could be concluded from the increase of P300 in the cue-reactivity condition among heroin addicts. Findings suggest that applying this paradigm in addiction studies benefits comprehensive evaluation of neuroelectrophysiological activity among addicts, which can promote a better understanding of drugs' effects on the brain as well as define new neuroelectrophysiological characteristics of addiction properties. © 2016 Wiley Periodicals, Inc.

Reward and punishment-based compound cue learning and generalization in opiate dependency.

Substance dependence is thought to be mediated by abnormalities in cognitive abilities, but how this impacts decision-making remains unclear. This study aimed to test whether people who are opiate dependent differed from never-dependent controls in learning from reward and punishment or in the generalization of learning to novel conditions. Participants with opiate dependency consisted of 21 people who were outpatients in a methadone maintenance program; the control group consisted of 21 healthy participants with no histories of substance abuse. Subjects completed a computer-based task that involved two phases: the training phase involved participants being presented with compound stimulus (a shape and color) in each trial, with the goal of learning which compounds to 'pick' for rewards or 'skip' to avoid punishment. The test phase involved a transfer test, where stimuli from the first phase were combined together to form novel compounds without feedback. The control group demonstrated fewer errors compared to opiate-dependent individuals during the training phase. In the test phase, controls used prior knowledge of both shapes and colors in responding; however, opiate-dependent individuals used shapes but did not use their knowledge of color to modulate responding. When performance during training was equated in the groups using a learning threshold, this difference between groups on the generalization test remained. A deficit in learning generalization might be indicative of group differences in learning strategies in operation during training; however, future work is necessary to uncover the specific neural substrates in action during transfer tasks, and to determine the effects of acute methadone dosage on decision-making.

The relationship between polymorphisms of BDNFOS and BDNF genes and heroin addiction in the Han Chinese population.

BACKGROUND: The number of heroin addicts is increasing in the world. Both environmental and genetic factors both play critical roles in the process of heroin addiction. We aimed to investigate the associations between single nucleotide polymorphisms (SNPs) in LIN7C, BDNFOS and BDNF genes and drug addiction in the Han Chinese population. METHODS: We conducted a case-control study among 692 cases and 700 healthy controls from Xi'an, China. Eight SNPs were selected and genotyped using MassARRAY technology (Sequenom, San Diego, CA, USA). Odds ratios (OR) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression adjusting for age and sex. RESULTS: Using the chi-squared test, we found that rs7481311 (OR =1.275, 95% CI = 1.087-1.497, p = 0.009) and rs11030096 (OR =1.227, 95% CI = 1.049-1.436, p = 0.011) in the BNDFOS were associated with an increased risk of heroin addiction. By contrast, rs988712 located in BDNFOS showed a decreased risk of heroin addiction (OR =0.734, 95% CI = 0.582-0.925, p = 0.003). By genetic model analysis, we found that the 'T' allele of rs988712 in BDNFOS had a protective role for heroin addiction in the additive model and dominant model (p < 0.05). By contrast, the allele 'T' of rs7481311 in BDNFOS significantly elevated the risk of heroin addiction in the additive model, recessive model and dominant model (p < 0.05). We also found that allele 'C' of rs11030096 was associated with an increased risk of addiction in the dominant model and additive model (p < 0.05). Additionally, we found that rs6265, rs11030104 and rs10767664 in BDNF were associated with a decreased risk of heroin addiction (p < 0.05). However, only rs7481311 in BDNFOS remained significant after Bonferroni correction (p < 0.00625). CONCLUSIONS: These results suggest that polymorphisms of BDNFOS play an important role in heroin addiction susceptibility in the Chinese Han population.

Transgenerational effects of paternal heroin addiction on anxiety and aggression behavior in male offspring.

BACKGROUND: Heroin addiction is a growing concern, affecting the socioeconomic development of many countries. Little is known about transgenerational effects on phenotype changes due to heroin addiction. This study aims to investigate changes in level of anxiety and aggression up to four different generations of adult male rats due to paternal exposure to heroin. METHODS: Male Sprague-Dawley rats were exposed with heroin intraperitoneally (i.p.) twice-daily for 14 days with increasing dosage regimen (F0-heroin). Male Sprague-Dawley rats (6-weeks-old) were divided into: (1) heroin exposed group (F0-heroin) and (2) control group treated with saline solution (F0-control). The dosage regime started with the lowest dose of 3 mg/kg per day of heroin followed by 1.5 mg/kg increments per day to a final dose of 13.5 mg/kg per day. Offspring were weaned on postnatal day 21. The adult male offspring from each generation were then mated with female-naïve rats after 2 weeks of heroin absence. Open field test and elevated plus maze test were used to study the anxiety level, whereas resident intruder test was used to evaluate aggression level in the addicted male rats and their offspring. RESULTS: Heroin exposure in male rats had resulted in smaller sizes of the litters compared to the control. We observed a higher anxiety level in the F1 and F2 progenies sired by the heroin exposed rats (F0) as compared to the control rats. Paternal heroin exposure also caused significantly more aggressive offspring in F1 compared to the control. The same pattern was also observed in the F2. CONCLUSION: Our results demonstrated that the progenies of F1 and F2 sustained higher levels of anxiety and aggression which are due to paternal heroin exposure.

ZNF804A variants confer risk for heroin addiction and affect decision making and gray matter volume in heroin abusers.

Drug addiction shares common neurobiological pathways and risk genes with other psychiatric diseases, including psychosis. One of the commonly identified risk genes associated with broad psychosis has been ZNF804A. We sought to test whether psychosis risk variants in ZNF804A increase the risk of heroin addiction by modulating neurocognitive performance and gray matter volume (GMV) in heroin addiction. Using case-control genetic analysis, we compared the distribution of ZNF804A variants (genotype and haplotype) in 1035 heroin abusers and 2887 healthy subjects. We also compared neurocognitive performance (impulsivity, global cognitive ability and decision-making ability) in 224 subjects and GMV in 154 subjects based on the ZNF804A variants. We found significant differences in the distribution of ZNF804A intronic variants (rs1344706 and rs7597593) allele and haplotype frequencies between the heroin and control groups. Decision-making impairment was worse in heroin abusers who carried the ZNF804A risk allele and haplotype. Subjects who carried more risk alleles and haplotypes of ZNF804A had greater GMV in the bilateral insular cortex, right temporal cortex and superior parietal cortex. The interaction between heroin addiction and ZNF804A variants affected GMV in the left sensorimotor cortex. Our findings revealed several ZNF804A variants that were significantly associated with the risk of heroin addiction, and these variants affected decision making and GMV in heroin abusers compared with controls. The precise neural mechanisms that underlie these associations are unknown, which requires future investigations of the effects of ZNF804A on both dopamine neurotransmission and the relative increases in the volume of various brain areas.

Abnormal gray matter volume and resting-state functional connectivity in former heroin-dependent individuals abstinent for multiple years.

Previous studies have suggested that heroin addiction is associated with structural and functional brain abnormalities. However, it is largely unknown whether these characteristics of brain abnormalities would be persistent or restored after long periods of abstinence. Considering the very high rates of relapse, we hypothesized that there may exist some latent neural vulnerabilities in abstinent heroin users. In this study, structural and resting-state functional magnetic resonance imaging data were collected from 30 former heroin-dependent (FHD) subjects who were drug free for more than 3 years and 30 non-addicted control (CN) volunteers. Voxel-based morphometry was used to identify possible gray matter volume differences between the FHD and CN groups. Alterations in resting-state functional connectivity in FHD were examined using brain areas with gray matter deficits as seed regions. Significantly reduced gray matter volume was observed in FHD in an area surrounding the parieto-occipital sulcus, which included the precuneus and cuneus. Functional connectivity analyses revealed that the FHD subjects showed reduced positive correlation within the default mode network and visual network and decreased negative correlation between the default mode network, visual network and task positive network. Moreover, the altered functional connectivity was correlated with self-reported impulsivity scores in the FHD subjects. Our findings suggest that disruption of large-scale brain systems is present in former heroin users even after multi-year abstinence, which could serve as system-level neural underpinnings for behavioral dysfunctions associated with addiction.

Gender Differences in Heroin Addiction and Treatment: Results from the VEdeTTE Cohort.

BACKGROUND: Gender differences strongly affect heroin addiction, from risk factors to patterns of consumption, access to treatments, and outcomes. OBJECTIVES: To investigate gender differences in the VEdeTTE cohort of heroin addicts. METHODS: VEdeTTE is a cohort of 10,454 heroin users enrolled between 1998 and 2001 in 115 public drug treatment centres in Italy. Clinical and personal information were collected at intake through a structured interview. Treatments were recorded using a standardized form. Gender differences were explored with regard to characteristics at intake, treatments, and retention in methadone maintenance and therapeutic community. Cox Proportional models were carried out to identify risk factors for treatment abandon. RESULTS: Compared with men, at their first access to treatment women with drug addiction were younger, more frequently married, legally separated, divorced or widow, unemployed though better educated, HIV+; more frequently they lived with their partner and sons. They reported a higher use of sedatives, but a lower use of alcohol; more frequently they had psychiatric comorbidity, including depression, self-injuries, and suicide attempts. Psychotherapy was more frequently prescribed to women, pharmacological treatments to men. Methadone maintenance was less frequently abandoned by women. Drug abuse severity factors predicted abandon of methadone among women. High methadone doses and the combination with psychotherapy improved treatment retention in both genders. Low education level and severity factors among women and young age among men predicted abandon of therapeutic community. CONCLUSIONS: Gender differences in the VEdeTTE cohort suggest the need of a gender sensitive approach to improve treatment outcomes among heroin addicts.

Nature of functional links in valuation networks differentiates impulsive behaviors between abstinent heroin-dependent subjects and nondrug-using subjects.

Advanced neuroimaging studies have identified brain correlates of pathological impulsivity in a variety of neuropsychiatric disorders. However, whether and how these spatially separate and functionally integrated neural correlates collectively contribute to aberrant impulsive behaviors remains unclear. Building on recent progress in neuroeconomics toward determining a biological account of human behaviors, we employed resting-state functional MRI to characterize the nature of the links between these neural correlates and to investigate their impact on impulsivity. We demonstrated that through functional connectivity with the ventral medial prefrontal cortex, the δ-network (regions of the executive control system, such as the dorsolateral prefrontal cortex) and the ß-network (regions of the reward system involved in the mesocorticolimbic pathway), jointly influence impulsivity measured by the Barratt impulsiveness scale scores. In control nondrug-using subjects, the functional link between the ß- and δ-networks is balanced, and the δ-network competitively controls impulsivity. However, in abstinent heroin-dependent subjects, the link is imbalanced, with stronger ß-network connectivity and weaker δ-network connectivity. The imbalanced link is associated with impulsivity, indicating that the ß- and δ-networks may mutually reinforce each other in abstinent heroin-dependent subjects. These findings of an aberrant link between the ß- and δ-networks in abstinent heroin-dependent subjects may shed light on the mechanism of aberrant behaviors of drug addiction and may serve as an endophenotype to mark individual subjects' self-control capacity.