Abnormal functional integration of thalamic low frequency oscillation in the BOLD signal after acute heroin treatment

Heroin addiction is a severe relapsing brain disorder associated with impaired cognitive control, including deficits in attention allocation. The thalamus has a high density of opiate receptors and is critically involved in orchestrating cortical activity during cognitive control. However, there have been no studies on how acute heroin treatment modulates thalamic activity. In a cross‐over, double‐blind, vehicle‐controlled study, 29 heroin‐maintained outpatients were studied after heroin and placebo administration, while 20 healthy controls were included for the placebo condition only. Resting‐state functional magnetic resonance imaging was used to analyze functional integration of the thalamus by three different resting state analysis techniques. Thalamocortical functional connectivity (FC) was analyzed by seed‐based correlation, while intrinsic thalamic oscillation was assessed by analysis of regional homogeneity (ReHo) and the fractional amplitude of low frequency fluctuations (fALFF). Relative to the placebo treatment and healthy controls, acute heroin administration reduced thalamocortical FC to cortical regions, including the frontal cortex, while the reductions in FC to the mediofrontal cortex, orbitofrontal cortex, and frontal pole were positively correlated with the plasma level of morphine, the main psychoactive metabolite of heroin. Furthermore, heroin treatment was associated with increased thalamic ReHo and fALFF values, whereas fALFF following heroin exposure correlated negatively with scores of attentional control. The heroin‐associated increase in fALFF was mainly dominated by slow‐4 (0.027–0.073 Hz) oscillations. Our findings show that there are acute effects of heroin within the thalamocortical system and may shed new light on the role of the thalamus in cognitive control in heroin addiction. Future research is needed to determine the underlying physiological mechanisms and their role in heroin addiction. Hum Brain Mapp 36:5287–5300, 2015. © 2015 Wiley Periodicals, Inc.     

Mouse strain differences in locomotor,sensitisation and rewarding effect of heroin; association with alterations in MOP‐r activation and dopamine transporter binding

There is growing agreement that genetic factors play an important role in the risk to develop heroin addiction, and comparisons of heroin addiction vulnerability in inbred strains of mice could provide useful information on the question of individual vulnerability to heroin addiction. This study examined the rewarding and locomotor‐stimulating effects of heroin in male C57BL/6J and DBA/2J mice. Heroin induced locomotion and sensitisation in C57BL/6J but not in DBA/2J mice. C57BL/6J mice developed conditioned place preference (CPP) to the highest doses of heroin, while DBA/2J showed CPP to only the lowest heroin doses, indicating a higher sensitivity of DBA/2J mice to the rewarding properties of heroin vs C57BL/6J mice. In order to investigate the neurobiological substrate underlying some of these differences, the effect of chronic ‘intermittent’ escalating dose heroin administration on the opioid, dopaminergic and stress systems was explored. Twofold higher μ‐opioid receptor (MOP‐r)‐stimulated [³⁵S]GTPγS binding was observed in the nucleus accumbens and caudate of saline‐treated C57BL/6J mice compared with DBA/2J. Heroin decreased MOP‐r density in brain regions of C57BL/6J mice, but not in DBA/2J. A higher density of dopamine transporters (DAT) was observed in nucleus accumbens shell and caudate of heroin‐treated DBA/2J mice compared with heroin‐treated C57BL/6J. There were no effects on D₁ and D₂ binding. Chronic heroin administration decreased corticosterone levels in both strains with no effect of strain. These results suggest that genetic differences in MOP‐r activation and DAT expression may be responsible for individual differences in vulnerability to heroin addiction.     

Differential regional effects of methadone maintenance compared to heroin dependence on mu-opioid receptor desensitization in rat brain

Methadone maintenance therapy has been the mainstay of treatment for heroin addiction since the 1970s. Recent studies indicate that methadone is of greater relative intrinsic efficacy than the active metabolites of heroin at mu-opioid receptors and that the extent of mu-opioid receptor desensitization is dependent upon agonist efficacy. Regional differences have been found for mu-opioid receptor desensitization with chronic heroin self-administration, and a similar paradigm was employed to compare regional differences between the effects of heroin and methadone. Rats were trained to self-administer heroin i.v., and the dose available was increased incrementally to a terminal value of 6 mg/kg for each infusion. Half of these rats were allowed to continue to self-administer heroin, while dependence was maintained in the others by hourly infusions of 3 mg/kg of methadone. A separate group of animals was kept on a low dose of heroin. Activation of G-proteins by the high efficacy agonist DAMGO was decreased to a greater extent in animals treated chronically with methadone compared with those allowed to self-administer heroin in amygdala, periaqueductal gray, and subicular nucleus. Activation of G-proteins by the partial agonist endomorphin was decreased in striatum, thalamus, and amygdala in rats from all drug treatment groups, but to a greater extent in the striatum in methadone treated rats compared with the heroin groups. Elucidating the mechanisms by which methadone induces differential desensitization of mu-opioid receptors across brain regions compared with heroin could provide insights to improve the pharmacotherapy of heroin addiction.     

Effects of cortisol administration on craving in heroin addicts

Heroin dependence is a severe and chronically relapsing substance use disorder with limited treatment options. Stress is known to increase craving and drug-taking behavior, but it is not known whether the stress hormone cortisol mediates these stress effects or whether cortisol may rather reduce craving, for example, by interfering with addiction memory. The aim of the present study was to determine the effects of cortisol administration on craving in heroin-dependent patients and to determine whether the effects depend on the daily dose of heroin consumption. We used a double-blind, placebo-controlled, cross-over study in 29 heroin-dependent patients in a stable heroin-assisted treatment setting. A single oral dose of 20 mg of cortisol or placebo was administered 105 min before the daily heroin administration. The primary outcome measure was cortisol-induced change in craving. Secondary measures included anxiety, anger and withdrawal symptoms. For the visual analog scale for craving, we found a significant interaction (P=0.0027) between study medication and heroin-dose group (that is, daily low, medium or high dose of heroin). Cortisol administration reduced craving in patients receiving a low dose of heroin (before heroin administration: P=0.0019; after heroin administration: P=0.0074), but not in patients receiving a medium or high dose of heroin. In a picture-rating task with drug-related pictures, cortisol administration did not affect the ratings for the picture-characteristic craving in all the three heroin-dose groups. Cortisol also did not significantly affect secondary outcome measures. In conclusion, a single administration of cortisol leads to reduced craving in low-dose heroin addicts. The present findings might have important clinical implications with regard to understanding stress effects and regarding treatment of addiction.     

Models of a heroin epidemic.

Heroin addiction may be considered an epidemic disease that is communicated by people who are addicted to the drug. It has been suggested that the most recent epidemic in the United States had its peak incidence in 1969. The age of heroin addicts entering treatment has increased systematically from 1973 to 1976 at a rate of less than one year of age per calendar year. This pattern is consistent with a moderate decline in a national heroin epidemic or a geographical migration of the epidemic from more to less populated areas. There are also seasonal trends in the age of admission to treatment.     

The medical complications of heroin use

PURPOSE OF REVIEW: Heroin use is associated with numerous adverse sequelae. As clinical services develop, addiction psychiatrists will increasingly be called upon to help identify and manage the complications of heroin use. This review focuses on recent research into the medical complications of heroin use and looks at strategies to minimize harm associated with this practice. RECENT FINDINGS: Mortality associated with heroin overdose has increased substantially in many countries. Parenteral use of opioid drugs is a central factor and other risk factors include polydrug use, particularly benzodiazepines and alcohol, mental health issues and environmental factors not conducive to resuscitation. Unravelling the determinants of blood-borne virus transmission continues, the focus shifting from needle sharing to inadvertent sharing of other injecting equipment. Trials addressing the challenges of antiviral therapy in injecting drug users are emerging. A greater understanding of the effects of opioids on immune functioning complements our knowledge of infection in the heroin-using group as well as possibly explaining the reduced response to vaccination in this group. SUMMARY: Medical complications of heroin affect a number of different organ systems. The role of the addiction specialist is to be aware of these so that early diagnosis and appropriate management is instituted. The latter will generally be done in collaboration with other specialists. The addictions specialist can play a significant role in the development of clinical systems to minimize these complications.     

Gamma-vinyl GABA (GVG) blocks expression of the conditioned place preference response to heroin in rats

We examined the effect of gamma-vinyl GABA (GVG) on the expression of the conditioned place preference response to intraperitoneally (i.p.) administered heroin in rats. Heroin, but not vehicle, produced a significant conditioned place preference response. Pretreatment of animals with 300 mg/kg of GVG significantly attenuated the expression of the heroin-induced conditioned place preference response. These results are the first to suggest that systemic GVG may provide an effective alternative to methadone maintenance in the treatment of heroin addiction, since it is without abuse potential and can be used for treatment outside an institutional setting.     

静息状态下海洛因成瘾者伏核功能连接的fMRI研究

目的 利用静息态功能磁共振成像(fMRI)技术分析海洛因成瘾者静息状态下与伏核有功能连接的脑区,以探讨海洛因成瘾者"奖赏系统"的组成.方法 选择安徽省戒毒所自2009年6月至2010年3月收治的自愿接受戒毒的海洛因成瘾患者15例作为成瘾组,同期健康体检者15例为对照组,进行静息态fMRI扫描后选取左、右侧伏核为感兴趣区(ROI)进行静息态脑功能连接分析,确定受试者静息状态下与双侧伏核有功能连接的相应脑区.结果 静息状态下成瘾组中与伏核有功能连接的脑区包括双侧丘脑、基底节区、海马、中脑以及对侧伏核等脑区(左侧伏核还与前扣带回有显著的功能连接);而对照组中与伏核有功能连接的脑区仅为海马和对侧伏核,而且激活程度明显小于成瘾组.结论 静息态下与伏核有功能连接的脑区构成了成瘾的"奖赏系统";静息态fMRI技术有助于了解与海洛因成瘾相关脑区之间的功能联系.     

Reduced grey matter in the posterior insula as a structural vulnerability or diathesis to addiction

A number of neuroimaging studies have shown that drug addiction is associated with morphological differences in several brain areas, including orbito-frontal and limbic structures. Most of these studies have investigated patients with addiction to cocaine. The neurobiological mechanisms which play a role in drug addiction are not fully understood, however, and the causal factors remain under investigation. The present study investigated morphological differences between patients with history of cocaine (N=14) and heroin (N=24) abuse and healthy matched controls (N=24). A 3D T1W MRI scan was acquired for all participants and the grey matter images of each patient group compared with those of controls. A direct comparison of the two addiction groups was also carried out. When compared with controls cocaine dependent patients had lower grey matter values in the left middle occipital gyrus, right putamen and insula, whereas heroin abusers had lower grey matter values in the right insula. The direct comparison between the two addiction groups showed that cocaine abusers had less grey matter in the right posterior cingulate, medio-temporal and cerebellar regions, whereas heroin abusers showed less grey matter in parietal regions on both sides, including postcentral gyrus and inferior parietal lobule. Reduced right posterior insular cortex was commonly found in both cocaine and heroin dependent patients. This morphological difference might represent a structural marker of addiction, which is independent of the discrete regional effects of each psychotropic substance of abuse, and might constitute a possible neurobiological vulnerability or diathesis to addiction. Equally, the discrete structural differences emerging from the direct comparison of cocaine and heroin abusers might reflect the effects of differential drug binding in the brain and/or express a form of neurobiological vulnerability which might explain individual drug choice.     

Abeta vaccine therapy for Alzheimer's disease]

In 1999, Schenk et al reported that vaccination of PDAPP-transgenic mice with synthetic Abeta42 in complete Freund's adjuvant showed markedly decrease of the amyloid burden in the brain. The second trial of vaccine, AN1792, for Alzheimer's patients was halted because of meningoencephalitis found in 6% of patients and one autopsy case was reported. Here, we comment the methods and the immunological mechanisms of Abeta vaccine therapy and discuss the pathological changes in the brain and side effects after AN1792 treatment. Furthermore, we present an oral Abeta vaccine therapy for Alzheimer's disease with the recombinant adeno-associated virus (AAV) vector that we developed.     

Increased functional connectivity in the resting-state basal ganglia network after acute heroin substitution

Reinforcement signals in the striatum are known to be crucial for mediating the subjective rewarding effects of acute drug intake. It is proposed that these effects may be more involved in early phases of drug addiction, whereas negative reinforcement effects may occur more in later stages of the illness. This study used resting-state functional magnetic resonance imaging to explore whether acute heroin substitution also induced positive reinforcement effects in striatal brain regions of protracted heroin-maintained patients. Using independent component analysis and a dual regression approach, we compared resting-state functional connectivity (rsFC) strengths within the basal ganglia/limbic network across a group of heroin-dependent patients receiving both an acute infusion of heroin and placebo and 20 healthy subjects who received placebo only. Subsequent correlation analyses were performed to test whether the rsFC strength under heroin exposure correlated with the subjective rewarding effect and with plasma concentrations of heroin and its main metabolites morphine. Relative to the placebo treatment in patients, heroin significantly increased rsFC of the left putamen within the basal ganglia/limbic network, the extent of which correlated positively with patients'' feelings of rush and with the plasma level of morphine. Furthermore, healthy controls revealed increased rsFC of the posterior cingulate cortex/precuneus in this network relative to the placebo treatment in patients. Our results indicate that acute heroin substitution induces a subjective rewarding effect via increased striatal connectivity in heroin-dependent patients, suggesting that positive reinforcement effects in the striatum still occur after protracted maintenance therapy.     

Neuroelectrophysiological approaches in heroin addiction research: A review of literatures

Neuroelectrophysiological properties have been used in human heroin addiction studies. These studies vary in their approach, experimental conditions, paradigms, and outcomes. However, it is essential to integrate previous findings and experimental methods for a better demonstration of current issues and challenges in designing such studies. This Review examines methodologies and experimental conditions of neuroelectrophysiological research among heroin addicts during withdrawal, abstinence, and methadone maintenance treatment and presents the findings. The results show decrements in attentional processing and dysfunctions in brain response inhibition as well as brain activity abnormalities induced by chronic heroin abuse. Chronic heroin addiction causes increased β and α2 power activity, latency of P300 and P600, and diminished P300 and P600 amplitude. Findings confirm that electroencephalography (EEG) band power and coherence are associated with craving indices and heroin abuse history. First symptoms of withdrawal can be seen in high‐frequency EEG bands, and the severity of these symptoms is associated with brain functional connectivity. EEG spectral changes and event‐related potential (ERP) properties have been shown to be associated with abstinence length and tend to normalize within 3–6 months of abstinence. From the conflicting criteria and confounding effects in neuroelectrophysiological studies, the authors suggest a comprehensive longitudinal study with a multimethod approach for monitoring EEG and ERP attributes of heroin addicts from early stages of withdrawal until long‐term abstinence to control the confounding effects, such as nicotine abuse and other comorbid and premorbid conditions. © 2016 Wiley Periodicals, Inc.     

Histone H3 phosphoacetylation is critical for heroin-induced place preference

We investigated the role of histone H3 phosphoacetylation in the nucleus accumbens (NAc) in heroin-conditioned place preference paradigm. Heroin could dose-dependently increase histone H3 phosphoacetylation specifically in the NAc and could enhance heroin place preference. Injection of trichostatin A into the NAc significantly augmented heroin-induced histone H3 phosphoacetylation and enhanced heroin place preference. Conversely, injection of MK-801 into the NAc attenuated histone H3 phosphoacetylation and reduced heroin place preference. These data suggest that histone H3 phosphoacetylation in the NAc may play a critical role in heroin addiction.     

Acupuncture inhibits cue-induced heroin craving and brain activation

Previous research using functional MRI has shown that specific brain regions associated with drug dependence and cue-elicited heroin craving are activated by environmental cues. Craving is an important trigger of heroin relapse, and acupuncture may inhibit craving. In this study, we performed functional MRI in heroin addicts and control subjects. We compared differences in brain activation between the two groups during heroin cue exposure, heroin cue exposure plus acupuncture at the Zusanli point (ST36) without twirling of the needle, and heroin cue exposure plus acupuncture at the Zusanli point with twirling of the needle. Heroin cue exposure elicited significant activation in craving-related brain regions mainly in the frontal lobes and callosal gyri. Acupuncture without twirling did not significantly affect the range of brain activation induced by heroin cue exposure, but significantly changed the extent of the activation in the heroin addicts group. Acupuncture at the Zusanli point with twirling of the needle significantly decreased both the range and extent of activation induced by heroin cue exposure compared with heroin cue exposure plus acupuncture without twirling of the needle. These experimental findings indicate that presentation of heroin cues can induce activation in craving-related brain regions, which are involved in reward, learning and memory, cognition and emotion. Acupuncture at the Zusanli point can rapidly suppress the activation of specific brain regions related to craving, supporting its potential as an intervention for drug craving.     

纳曲酮用于海洛因依赖者抗复吸治疗的结果分析

目的了解纳曲酮抗复吸治疗效果。方法采用回顾性临床资料分析方法，分析145例阿片类药物依赖后自愿戒断使用纳曲酮脱瘾及抗复吸治疗的临床资料。结果纳曲酮对于有固定职业、戒毒愿望强烈、家庭关注较多和个人支持系统相对较好抗复吸疗效好，能明显延长探亲时间，减少吸毒冲动，觅药行为，无明显副作用。结论纳曲酮在抗复吸中有很好的运用前景。     

Assessing the Role of Corticothalamic and Thalamo-Accumbens Projections in the Augmentation of Heroin Seeking in Chronically Food-Restricted Rats

Drug addiction is a chronic disorder characterized by compulsive drug seeking, and involves repetitive cycles of compulsive drug use, abstinence, and relapse. In both human and animal models of addiction, chronic food restriction increases rates of relapse. Our laboratory has reported a robust increase in drug seeking following a period of withdrawal in chronically food-restricted rats compared with sated controls. Recently, we reported that activation of the paraventricular nucleus of the thalamus (PVT) abolished heroin seeking in chronically food-restricted rats. However, the precise inputs and outputs of the PVT that mediate this effect remain elusive. The goal of the current study was to determine the role of corticothalamic and thalamo-accumbens projections in the augmentation of heroin seeking induced by chronic food restriction. Male Long–Evans rats were trained to self-administer heroin for 10 d. Next, rats were removed from the self-administration chambers and were subjected to a 14 d withdrawal period while sated (unlimited access to food) or mildly food-restricted (FDR). On day 14, rats were returned to the self-administration context for a 3 h heroin-seeking test under extinction conditions during which corticothalamic and thalamo-accumbens neural activity was altered using chemogenetics. Surprisingly, chemogenetic activation or inhibition of corticothalamic projections did not alter heroin-seeking behavior. Chemogenetic activation of thalamo-accumbens shell, but not core, projectors attenuated heroin seeking in FDR rats. The results indicate an important role for the PVT to nucleus accumbens shell projections in the augmentation of heroin seeking induced by chronic food restriction.SIGNIFICANCE STATEMENT Relapse to heroin use is one of the major obstacles in the treatment of opiate addiction. Triggers for relapse are modulated by environmental challenges such as caloric restriction. Elucidating the brain mechanisms that underlie relapse is critical for evidence-based treatment development. Here we demonstrate a critical role for the input from the paraventricular thalamus (PVT), a hub for cortical, sensory, and limbic information, to the nucleus accumbens shell (an area known to be important for reward and motivation) in the augmentation of heroin seeking in food-restricted rats. Our findings highlight a previously unknown role for the PVT in heroin seeking following a period of abstinence.     

Diffusivity of the uncinate fasciculus in heroin users relates to their levels of anxiety

Heroin use is closely associated with emotional dysregulation, which may explain its high comorbidity with disorders such as anxiety and depression. However, the understanding of the neurobiological etiology of the association between heroin use and emotional dysregulation is limited. Previous studies have suggested an impact of heroin on diffusivity in white matter involving the emotional regulatory system, but the specificity of this finding remains to be determined. Therefore, this study investigated the association between heroin use and diffusivity of white matter tracts in heroin users and examined whether the tracts were associated with their elevated anxiety and depression levels. A sample of 26 right-handed male abstinent heroin users (25 to 42 years of age) and 32 matched healthy controls (19 to 55 years of age) was recruited for this study. Diffusion tensor imaging data were collected, and their levels of anxiety and depression were assessed using the Hospital Anxiety and Depression Scale. Our findings indicated that heroin users exhibited higher levels of anxiety and depression, but the heroin use-associated left uncinate fasciculus was only related to their anxiety level, suggesting that association between heroin and anxiety has an incremental organic basis but that for depression could be a threshold issue. This finding improves our understanding of heroin addiction and its comorbid affective disorder and facilitates future therapeutic development.     

Chronic naltrexone suppresses platelet aggregation induced by adrenaline and 5-hydroxytryptamine in former heroin addicts

Summary Naltrexone, an opioid receptor antagonist, is used as an adjunct in the treatment of opiate addiction. In former heroin addicts, long-term treatment with naltrexone (350 mg/week for 5 months) resulted in suppression of adrenaline and 5-hydroxytryptamine (5-HT)-induced platelet aggregation. The results demonstrate that sustained blockade of opioid receptors can impair the functional expression of ₂-adrenoceptors and 5-HT₂ receptors in human platelets. These findings may have negative clinical implications in the treatment of opiate addiction with naltrexone.