成瘾药物行为敏化及机制

反复、间断给予依赖性药物(如吗啡、苯丙胺、可卡因、尼古丁、酒精等)后,能增强实验动物的自发性活动反应(locomotor response),这种伴随着反复给药而出现的行为反应增强被称为行为敏化(behavioral sensitization).行为敏化的形成和表达与药物成瘾有着重要的关系,目前已经证明成瘾药物诱导的行为敏化对觅药行为和复吸的发生和维持有着重要的影响[1].敏化动物模型已经为研究药物成瘾的神经生物学机制提供了重要的实验手段[2].那么行为敏化是怎样形成的?它在药物成瘾中扮演的是个什么角色?环境因素在行为敏化中的作用又如何?这些问题的回答将有助于我们更好的理解敏化行为在药物成瘾中的作用.     

应激对药物自身给药的影响

解释依赖性药物从正常应用转向滥用并导致成瘾的理论主要有两个 ,即药物中心观点和个体中心观点。药物中心观点认为药物滥用是由于慢性摄入依赖性药物 ,导致脑功能改变 ,从而表现出耐受、敏化和依赖状态。个体中心观点认为药物滥用是预先存在的病理条件被药物诱发 ,成瘾现象仅发生于特定个体是因为他们的生物学特性对依赖性药物发生了病理性反应 ,这使得他们较普通个体对依赖性药物更具滥用倾向。研究应激对药物成瘾的影响属于个体中心观点。研究已表明个体生物学状态决定了药物自身给药发展的可能性 ,并且在诱导追求药物的行为形成中 ,环境…     

NMDA受体与成瘾药物行为敏化的关系

行为敏化（behavioralsensitization）是指反复、间断给予依赖性药物（如可卡因、苯丙胺、吗啡等）后，动物对药物的行为反应增强，其主要表现为在封闭环境中的活动量上升或反复的小幅度刻板运动（咀嚼、舔、摇头等）。研究资料显示：介导药物行为敏化效应与调节药物奖赏效应的神经基质几乎完全重合。Robinson等人提出的动机一敏化（incentivesensitization）理论认为：导致成瘾的关键性神经改变是大脑奖赏系统对药物和药物相关刺激超敏。因此，行为敏化模型已在药物依赖性的评价中得到广泛应用，成为成瘾领域的一个研究热点。     

我国药物滥用与成瘾的流行现状及趋势研究新进展

<正>药物滥用和药物成瘾已成为当今世界性的公共卫生问题和严重的社会问题,并引起人们的广泛关注和高度警觉。药物滥用(drug abuse)是指非医疗目的反复、大量使用具有依赖性特性或依赖性潜力的药,为的是体验该药物产生的特殊精神效应,并由此导致精神依赖性和躯体依赖性[1]。药物成瘾是一种机体反复与药物接触引起的慢性复发性脑病,其主要特点是强迫性药物使用、持续性渴求状态和对药物渴求控制力的减弱[2]。药物滥用与成瘾的     

一针吗啡会改变你的一生吗?

在现实生活和临床工作中,我们常常可以观察到这样一种现象:酒香可以勾起酒精成瘾者强烈的饮酒欲望和冲动,白花花的粉末状物质或注射针头可以唤起吸毒病人对海洛因急迫的用药想法和渴求。这种对成瘾性物质需求敏感性的增加,实际上就是滥用药物动机的增强,即药物滥用动机敏化(motivation sensitization)。在动物上,则表现为对药物诱导的行为反应性明显增强(如海洛因、吗啡诱导大、小鼠的高活动性),即行为敏化(behavioral sensitization)。行为敏化与药物成瘾的某些特征(如强迫性用药、觅药行为),尤其是,与长时间停药后的复吸行为密切相关,是药物成瘾动物的重要行为特征之一。因此,作为研究药物成瘾神经生物学机制的一种动物模型,行为敏化已日益受到人们的关注。本课题组率先建立了单针吗啡诱导的小鼠行为敏化模型,发现吗啡预处理后,存在3～4 d的孵育阶段,可以促进短暂的药理作用向长时程的行为效应转化。单针吗啡给药所诱导的小鼠外在行为的改变具有持续时间长(至少21 d)、行为反应明显、重复性和稳定性较好的特点。在此模型基础上,进一步探讨单针吗啡诱导小鼠行为敏化的神经生物学机制,研究结果表明单针吗啡诱导小鼠行为敏化的形成涉及到新的基因转录、新的蛋白合成,以及组蛋白乙酰化修饰的改变。单针吗啡诱导行为敏化的形成过程中包括两个期:易损期和稳定期。Hsp70在单针吗啡诱导行为敏化形成过程中的易损期内发挥了至关重要的作用。基于本课题组已取得的实验数据和相关研究资料,我们提出了一个崭新的观点,即"分子伴侣介导阿片成瘾(molecular chaperone-mediated opioid addic-tion)"理论。介导神经/行为可塑性可能是分子伴侣Hsp70一个新的生理功能。当然,分子伴侣介导短暂药理作用(单针给药)与长时程行为改变(行为敏化)的分子药理学机制还有待进一步研究。     

药物依赖的表观调控研究现状和应用前景

药物滥用是目前严重的社会问题之一,药物滥用导致特定大脑区域的基因表达异常,造成具有特定功能的脑区在分子、细胞乃至整体水平的改变,从而促进药物依赖和成瘾行为。表观遗传修饰是指在长期持续刺激下诱导产生基因的表达变化的调控方式,其在药物滥用的各阶段有不同的变化规律和调控作用,可能是导致药物滥用的重要因素。本文综述近年来药物成瘾和依赖相关的表观遗传研究,旨在探讨通过表观遗传调控系统抑制和逆转药物滥用的靶点和策略。     

用药环境对药物敏化效应的调控作用

用药环境在精神活性物质诱导的行为敏化效应中发挥重要作用。新异环境和匹配环境能明显调节药物诱导的行为敏化,使药物产生敏化的量效曲线左移。环境的调控作用表明成瘾记忆参与了行为敏化的形成过程。该文就用药环境对药物敏化的作用及机制作一综述。     

药物滥用预防与科学、文化和伦理道德问题的关联(英文)

近年来在脑与行为领域的科学进展和发现已经革新了我们对于物质滥用及其对人体思维和情绪作用的知识。与此同时,针对促进药物滥用和成瘾发展的人类行为和环境的大量心理学和社会文化方面的研究也在展开。文化因素也被认为在世界不同地区成瘾行为的发展和上升中起重要作用。要采取有效的策略解决全球非法药物滥用与成瘾问题,我们需要一种整合和统一的视角,这种视角不仅包括科学,还应包括文化,伦理道德和精神等社会组成部分。药物滥用是一个涉及多方面的问题。它可以是生物因素和基因缺陷的结果,也可以是由于社会影响,药物的易获得性,文化压力等因素导致的习惯性行为。因此,针对药物滥用或成瘾者进行预防、治疗和康复的任何成功的计划都应该考虑到多方面的因素。科学研究在解释分子生物学、脑影像学等在药物滥用形成耐受和依赖的发展过程中的重要性方面已经取得了一定进展,该领域的研究还阐释了基因发挥作用并将成瘾的特性传递给后代的途径。然而科学对于药物滥用预防的贡献是有限的,因为这是一个需要综合心理干预和咨询的领域。文化在指导人们的态度和形成成瘾或戒断的潜在动机中发挥了核心作用。个体的戒断和康复部分依赖于文化环境。事实上,对非法药物的界定在不同文化中也各不相同。每个社会都建立了控制人们接触药物和酒精的行为规范。因此,在对药物滥用多角度、综合的预防和干预措施中,理解不同的文化期待、态度和行为规范是至关重要的。伦理道德和精神文明也是药物滥用预防中重要的因素。非治疗用的处方药物就是药物滥用领域中存在的伦理问题。另外,关于非法药物滥用的立法问题也在各个国家引起了严重的争议。伦理和科学不是互斥的关系,两者都在为大多数人的利益努力寻求真理。统揽科学、文化、伦理道德和精神文明对于预防药物滥用和成瘾康复有重要的意义。主要文明体系的和睦关系将带来更为有效的策略,以克服由于药物滥用问题蔓延导致的全球性危机。     

miRNA对药物成瘾行为的调控

目的介绍miRNA调控药物成瘾行为的研究进展。方法对最近关于基因表达转录后调控机制对成瘾行为的影响的研究进展作出归纳和总结。结果药物能诱导miRNA表达水平的变化,而成瘾相关脑区中miRNA表达的改变则参与了对成瘾行为的调节。结论 miRNA调控药物成瘾行为的研究对于揭示药物滥用等精神疾病的病理机制、治疗慢性药物依赖具有重大意义。     

常见药物成瘾与滥用的分析及中毒救治要点

不合理使用精神药物可产生许多问题，常见的有药物成瘾和药物滥用。近年来，导致药物成瘾和药物滥用的常见精神药物有阿片类药物、苯二氮革类药物、苯丙胺、苯环己哌啶、氯胺酮、γ-羟基丁酸盐。该文对这6种精神药物成瘾及滥用的诊断与中毒救治进行了分析，对于临床合理应用精神药物具有重要的实际意义。     

Drug wanting: behavioral sensitization and relapse to drug-seeking behavior

Repeated exposure to drugs of abuse enhances the motor-stimulant response to these drugs, a phenomenon termed behavioral sensitization. Animals that are extinguished from self-administration training readily relapse to drug, conditioned cue, or stress priming. The involvement of sensitization in reinstated drug-seeking behavior remains controversial. This review describes sensitization and reinstated drug seeking as behavioral events, and the neural circuitry, neurochemistry, and neuropharmacology underlying both behavioral models will be described, compared, and contrasted. It seems that although sensitization and reinstatement involve overlapping circuitry and neurotransmitter and receptor systems, the role of sensitization in reinstatement remains ill-defined. Nevertheless, it is argued that sensitization remains a useful model for determining the neural basis of addiction, and an example is provided in which data from sensitization studies led to potential pharmacotherapies that have been tested in animal models of relapse and in human addicts.     

Historical review: Molecular and cellular mechanisms of opiate and cocaine addiction

The National Institute on Drug Abuse was founded in 1974, and since that time there have been significant advances in understanding the processes by which drugs of abuse cause addiction. The initial protein targets for almost all drugs of abuse are now known. Animal models that replicate key features of addiction are available, and these models have made it possible to characterize the brain regions that are important for addiction and other drug effects, such as physical dependence. A large number of drug-induced changes at the molecular and cellular levels have been identified in these brain areas and rapid progress is being made in relating individual changes to specific behavioral abnormalities in animal models of addiction. The current challenges are to translate this increasingly impressive knowledge of the basic neurobiology of addiction to human addicts, and to identify the specific genes that make some individuals either particularly vulnerable or resistant to addiction. In this article, I present a historical review of basic research on opiate and cocaine addiction.     

The role of metabotropic glutamate receptors in drug reward, motivation and dependence

Addiction to drugs of abuse is a disorder that involves dysfunctions in motivational processes. Both the primary rewarding effects of drugs, as well as the acquired motivational properties of stimuli associated with drug-seeking and -taking, contribute to the perpetuation of dependence on drugs of abuse. Metabotropic glutamate (mGlu) receptors, which mediate slow glutamate neurotransmission, are located throughout limbic and cortical brain sites implicated in drug addiction. Preclinical evidence suggests that mGlu receptors play a crucial role in regulating behavioral effects of drugs of abuse relevant to drug addiction. Specifically, antagonists at excitatory postsynaptic mGlu5 receptors decrease drug self-administration without affecting motor behaviors, cognition or the reward value of natural rewards, while agonists at inhibitory presynaptic mGlu2/3 receptor agonists prevent reinstatement to drug-seeking and -taking after a period of abstinence. These findings have increased our understanding of the neuropathological processes associated with aspects of dependence on drugs of abuse and have provided new targets for pharmacological approaches to the treatment of dysfunctions in motivational processes characterizing the various phases of drug addiction.     

Fentanyl abuse and dependence: further evidence for second hand exposure hypothesis

We have proposed a novel hypothesis regarding the potential role of occupational or second-hand exposure in physician substance use, abuse, and addiction. While only 5.6% of licensed physicians in Florida are anesthesiologists, nearly 25% of physicians followed for substance abuse/dependence are anesthesiologists. When we sort by drug of choice, anesthesiologists have more opioid abuse and dependence than other physicians and appropriate controls. Abuse of one opioid, fentanyl, appears to be increasing and has been noted among the State of Florida's causes of opioid deaths. Fentanyl and sufentanyl are commonly administered highly potent opioid analgesics, as much as 80-800 times as potent as morphine. We have recent data from the State of Florida impaired physicians database, which has allowed us to categorize all fentanyl abusing and/ or dependent physicians. Just knowing that a physician abuses fentanyl gives you a good clue as to their specialty; 75% are anesthesiologists! While drug abuse researchers, oncologists and others who handle drugs of abuse everyday, have no greater incidence of opioid abuse or dependence, anesthesiologists are at the top of every list. Can this be due to just access and stress? We have proposed an alternative hypothesis of second hand exposure. To test this hypothesis, we developed a sensitive LC/MS/MS assay to measure the intravenous anesthetic and analgesic agents, propofol and fentanyl in air. Not only did we detect propofol and fentanyl in cardiovascular surgery operating room air, we also found the highest concentrations were close to the patient's mouth where anesthesiologists work for hours. Like tobacco, second hand opioid exposure can sensitize and change the brain making abuse, dependence and behavioral disorders more likely. Thus environmental exposure and sensitization may be an important risk factor in physician addiction. Second hand exposure may affect treatment outcome and explain anesthesiologist's inability to return to work in the operating room. We are developing an animal model for second hand exposure and additional studies of the operating room and cardiac anesthesiologists are underway.     

Regulation of drug taking by sensitization and habituation

The authors argue that drug taking is an operant behavior that is reinforced by the drug itself. The effectiveness of a drug as a reinforcer is modulated by sensitization and habituation to the drug as it is consumed. According to this model, drug taking stops when habituation reduces the ability of the drug to reinforce its own consumption. Drug taking resumes when spontaneous recovery restores the effectiveness of the drug as a reinforcer. This parsimonious model provides a framework for understanding many findings in the drug literature, including acute and chronic tolerance, the effect of deprivation on consumption, the contextual specificity of tolerance, polydrug abuse, cross-sensitization between stress and drugs, behavioral sensitization, priming, and reinstatement. Although this model cannot explain all aspects of drug taking (e.g., the effect of cognitive manipulations), it has many implications for understanding and controlling human drug consumption and addiction.     

精神活性物质成瘾的行为医学研究

本课题建立吗啡,甲基苯丙胺以及可卡因诱导的大、小鼠行为敏化模型。探讨了L-型钙通道阻滞剂,情绪稳定剂(锂盐,丙戊酸钠和卡马西平),以及新型μ受体部分激动剂噻吩诺啡对行为敏化形成,转化以及表达的影响。利用行为敏化模型,率先开展了曲马朵和槟榔嚼块提取物多药滥用的精神药理学研究。此外,在条件性位置偏爱和纳洛酮促吗啡戒断动物模型上,发现钙调蛋白抑制剂具有明显的干预作用,钙调蛋白可能是阿片类物质依赖治疗的新的分子靶点。与澳大利亚成瘾神经科学的合作研究发现,GABAB受体正性别构调节剂CGP9730可以抑制嗜酒大鼠的自饮酒行为,具有潜在的治疗酒精依赖与成瘾的临床应用价值。     

Conditioned locomotion is not correlated with behavioral sensitization to cocaine: an intra-laboratory multi-sample analysis.

Pre-clinical and clinical studies have demonstrated the importance of associative factors in regulating craving for drugs of abuse. To model these conditioned effects, we have examine cue-induced conditioned locomotion in rodents. The present study involved analysis of several of our prior studies to evaluate the relationship between conditioned locomotion and behavioral sensitization using a within-subjects analysis. Both are animal models used to study addiction, so it is important to know if one is predictive of the other, and more generally, if drug effects are predictive of conditioned effects. In all of our studies, Paired subjects received cocaine during presentation of conditioned stimuli while Unpaired subjects received saline with the stimuli and cocaine at the home cages an hour later. Paired subjects typically displayed behavioral sensitization over the course of training. After the completion of training, all subjects were tested with the conditioned stimuli in the absence of drug and conditioned locomotion was measured. The response of Unpaired subjects on the last training day was positively correlated with their response on test day, as expected since both days were nearly identical (stimuli presented without cocaine). However, for Paired subjects, the magnitude of conditioned locomotion on the drug-free test day was not positively correlated with the magnitude of behavioral sensitization. These results underscore the importance of focusing research on drug-free conditioned behaviors when attempting to model conditioned responses to drug related cues in human addicts.     

Dissociable roles of mGlu5 and dopamine receptors in the rewarding and sensitizing properties of morphine and cocaine

Rationale  

Drugs of abuse are initially used because of their rewarding properties. As a result of repeated drug exposure, sensitization to certain behavioral effects of drugs occurs, which may facilitate the development of addiction. Recent studies have implicated the metabotropic glutamate receptor 5 (mGlu5 receptor) in drug reward, but its role in sensitization is unclear. Stimulation of dopamine receptors plays an important role in drug reward, but not in the sensitizing properties of cocaine and morphine.     

The neurocircuitry of addiction: an overview

Drug addiction presents as a chronic relapsing disorder characterized by persistent drug-seeking and drug-taking behaviours. Given the significant detrimental effects of this disease both socially and economically, a considerable amount of research has been dedicated to understanding a number of issues in addiction, including behavioural and neuropharmacological factors that contribute to the development, loss of control and persistence of compulsive addictive behaviours. In this review, we will give a broad overview of various theories of addiction, animal models of addiction and relapse, drugs of abuse, and the neurobiology of drug dependence and relapse. Although drugs of abuse possess diverse neuropharmacological profiles, activation of the mesocorticolimbic system, particularly the ventral tegmental area, nucleus accumbens, amygdala and prefrontal cortex via dopaminergic and glutamatergic pathways, constitutes a common pathway by which various drugs of abuse mediate their acute reinforcing effects. However, long-term neuroadaptations in this circuitry likely underlie the transition to drug dependence and cycles of relapse. As further elucidated in more comprehensive reviews of various subtopics on addiction in later sections of this special issue, it is anticipated that continued basic neuroscience research will aid in the development of effective therapeutic interventions for the long-term treatment of drug-dependent individuals.