关于手术戒毒规范化开展的思考

吸毒成瘾是严重的医学和社会学问题。国内、外对吸毒成瘾采取的治疗方案由脱毒、防复吸和回归社会三个相互关联的方法构成。但收效甚微,复吸率居高不下。西安第四军医大学唐都医院神经外科在动物实验和借鉴以往经验的基础上,将立体定向技术用于毁损脑内与毒品心理依赖密切相关的关键位点的异常部分,对其异常功能进行调整,从而达到彻底戒毒的目的,取得了良好的疗效。本文介绍了手术戒毒在我国的发展历史,提出了规范化开展手术戒毒的建议。     

工作记忆训练对药物成瘾者认知功能的改善及其机制

对处于戒断期的各类药物成瘾群体进行认知训练，训练后药物成瘾个体认知能力得到改善，成瘾症状也得到了一定缓解。认知训练能够加速药物成瘾者大脑受损区域的自发性恢复，尤其是使影响个体抑制控制能力的中脑边缘多巴胺系统和前额叶系统发生功能性和结构性的积极变化，实现药物成瘾个体高级认知能力的改善。今后可以从不同类别的药物成瘾是否全部具有可逆性，设置的认知训练任务能否起到改善认知能力的效果，药物成瘾个体训练的性别差异以及训练效果的保持时间等角度进行研究。     

Developmental effects of acute, chronic, and withdrawal from chronic nicotine on fear conditioning

Pre-adolescence and adolescence are developmental periods associated with increased vulnerability for tobacco addiction, and exposure to tobacco during these periods may lead to long-lasting changes in behavioral and neuronal plasticity. The present study examined the short- and long-term effects of nicotine and nicotine withdrawal on fear conditioning in pre-adolescent, adolescent, and adult mice, and potential underlying substrates that may mediate the developmental effects of nicotine, such as changes in nicotinic acetylcholine receptor (nAChR) binding, CREB expression, and nicotine metabolism. Age-related differences existed in sensitivity to the effects of acute nicotine, chronic nicotine and nicotine withdrawal on contextual fear conditioning (no changes in cued fear conditioning were seen); younger mice were more sensitive to the acute effects and less sensitive to the effects of nicotine withdrawal 24 h post treatment cessation. Developmental differences in nAChR binding were associated with the effects of nicotine withdrawal on contextual learning. Developmental differences in nicotine metabolism and CREB expression were also observed, but were not related to the effects of nicotine withdrawal on contextual learning 24 h post treatment. Chronic nicotine exposure during pre-adolescence or adolescence, however, produced long-lasting impairments in contextual learning that were observed during adulthood, whereas adult chronic nicotine exposure did not. These developmental effects could be related to changes in CREB. Overall, there is a developmental shift in the effects of nicotine on hippocampus-dependent learning and developmental exposure to nicotine results in adult cognitive deficits; these changes in cognition may play an important role in the development and maintenance of nicotine addiction.     

药物成瘾行为的脑机制及其研究进展

药物成瘾是脑内相关核团和细胞在药物反复作用下发生适应性变化的时间依赖过程。成瘾的适应性学说从ｃＡＭＰ水平调节、阿片和多巴胺受体与Ｇ蛋白家族耦联等方面,为成瘾形成机制提供了最基本的生物学范畴的理论解释。实验证据在一定程度上揭示了从给药到耐受、敏感、依赖,再到撤药症状的生物变化过程。然而,阐明从急性给药到特殊脑区持续性的适应机制仍然是当前成瘾研究最具挑战性的目标之一。     

Intraadministration associations: conditional hyperalgesia elicited by morphine onset cues

There is evidence that exteroceptive cues associated with drug administration elicit conditional compensatory responding (e.g., hyperalgesia in organisms with a history of morphine administration). Recently it has become apparent that, within each administration, interoceptive early-drug onset cues (DOCs) may become associated with the later, larger drug effect (intraadministration associations). The present experiments evaluated DOC-elicited conditional hyperalgesia in rats intravenously infused with morphine. The results indicated that DOC-elicited hyperalgesia contributes to tolerance to the analgesic effect of morphine, and such DOC-elicited hyperalgesia is an associative phenomenon, rather than a sensitized response to the opiate. The findings suggest that associative analyses of tolerance should acknowledge the conditional responding elicited by DOCs, and extinction-based addiction treatments should incorporate extinction of DOC-elicited conditional responding.     

Effects of daily morphine administration and deprivation on choice and demand for remifentanil and cocaine in rhesus monkeys

Choice procedures have indicated that the relative reinforcing effectiveness of opioid drugs increases during opioid withdrawal. The demand curve, an absolute measure of reinforcer value, has not been applied to this question. The present study assessed whether mild morphine withdrawal would increase demand for or choice of remifentanil or cocaine. Four rhesus monkeys chose between remifentanil and cocaine during daily sessions. Demand curves for both drugs were subsequently obtained. The effects of daily injections of 3.2 mg/kg morphine on both choice and demand for these drugs was assayed 3 and 20.5 hr after each morphine injection, and then during a postmorphine period. Three hours following morphine injections, choice of remifentanil over cocaine decreased and demand for remifentanil--but not cocaine--became more elastic. During morphine withdrawal (20.5 hr postinjection), choice of remifentanil increased and remifentanil demand became more inelastic in 3 of 4 monkeys. Cocaine demand also became more inelastic during this period. Four to five weeks following the morphine regimen, demand for both drugs was more inelastic relative to the initial determination. The results suggest that both the relative and absolute reinforcing effectiveness of remifentanil decreased following morphine administration and increased during morphine withdrawal. The absolute reinforcing effectiveness of cocaine also increased during morphine withdrawal. In addition, extended exposure to drug self-administration and/or exposure to the morphine regimen produced long-term increases in demand for both drugs.     

"A new deal for the drug addict": the Addiction Research Center, Lexington, Kentucky

This article describes the social organization of knowledge production in the formative moments of the substance abuse research enterprise. It describes the institutional arrangements and material conditions of a U.S. Public Health Service laboratory that was housed in a facility run jointly with the federal Bureau of Prisons. The Addiction Research Center (ARC) in Lexington, Kentucky, was dedicated to elucidating the basic underlying mechanisms of drug addiction. The ARC was housed on the rural campus of a prison-hospital called "Narco," one of two "narcotics farms" in Lexington, Kentucky, and Fort Worth, Texas. For its studies on drug effects, the ARC had access to a pool of drug-experienced human subjects drawn from the ranks of convicted felons. Given their unparalleled access to human subjects, the scientists who worked at the ARC made conceptual contributions still acknowledged today. Based on archival work as well as dozens of oral history interviews with individuals who began their research careers at Lexington, the article presents an analytic, intellectual history of the early work of Abraham Wikler, whose lifelong pursuit of the underlying mechanisms of opiate addiction led him to hypothesize the role of conditioning in relapse, as an exemplar of the kind of scientific research that depended on closely listening to and observing "post-addicts," as subject participants were called.     

LISTENING TO NICOTINE:

Abstract— In recent years, theoretical models of drug motivation and drug dependence have downplayed the role of withdrawal symptoms in the maintenance of addiction. During this same period, strong links between drug use and measures of negative affect have been uncovered in empirical research. In this article we examine these trends in the context of research on smoking. Evidence is presented from two recent studies on smoking relapse that highlight the intimate connection between withdrawal symptomatology and negative affect Specifically, these studies reveal that (a) single-occasion measures of withdrawal symptoms or other markers of physical dependence do not contribute incremental validity in preceding relapse relative to measures of negative affect (b) the trajectory of withdrawal symptoms is highly idiosyncratic, (c) exacerbations cannot be tightly coupled with pharmacological events. (d) the temporal dynamics of withdrawal reflect fluctuations in negative affect, and (e) differences in the trajectory of withdrawal symptoms index relapse vulnerability. We conclude that a broadened view of withdrawal recognizing its probable affective bases will enhance its explanatory power and suggest new treatment strategies.     

Remodeling of the neuronal circuits underlying opiate-withdrawal memories following remote retrieval

Several types of memory display time-dependent reorganization of their underlying neural substrates, but it remains unclear whether affective memories associated with drug effects also follow similar reorganization. Here, we analyzed the neural circuits reactivated by the re-exposure of former dependent rats to the withdrawal-paired environment 1month after conditioning (remote memory) as compared with recent memory (Frenois, F., Stinus, L., Di Blasi, F., Cador, M., & Le Moine, C. (2005) A specific limbic circuit underlies opiate withdrawal memories The Journal of Neuroscience, 25, 1366-1374). C-fos expression showed that the circuits involved in the retrieval of withdrawal memories are partly different when comparing recent and remote reactivation, showing that, like other type of memories, affective memories linked to opiate withdrawal undergo anatomical reorganization, with a shift from extended amygdala regions toward cortical areas.     

Conditioning of successive adaptive responses to the initial effects of drugs

Data in the literature indicate that conditioned responses (CRs) generated by repeated pairing of conditional stimulus (CS) with administration of a neurotropic drug may resemble its unconditional effects or they may be opposite in direction; furthermore, the CRs may change as such pairings are continued. In explanation, it is hypothesized that as in conditioning of physiological reflexes, a CS repeatedly paired with administration of a neurotropic drug eventually comes to activate central“processing” events that are evoked by the“stimulus” properties of the drug,i.e., the effects of the drug at receptor sites inside or outside the pia mater which lie in the afferent arms of“reflex” neural circuits; or, the CS comes to activate central processing events that are evoked by centripetal feedback responses to the effects of the drug at receptor sites in the processing or efferent arms of reflex neural circuits. Depending on the receptor site action of the drug, the conditioned autonomic and/or neuromuscular responses that are observed may be in the same direction as, or opposite in direction to the unconditioned effects of the drug. With continued pairings of CS and drug, the unconditioned processing events evoked by the stimulus properties of the drug, and hence the CRs also, change in consequence of compensatory (sometimes“overshooting”) biochemical alterations proximal to the receptor site of action of the drug, induced by negative or positive neuronal feedback mechanisms. These concepts are utilized in a theory of opiate addiction and relapse.     

Role of dopamine,the frontal cortex and memory circuits in drug addiction: insight from imaging studies

Drug addiction is characterized by a set of recurring processes (intoxication, withdrawal, craving) that lead to the relapsing nature of the disorder. We have used positron emission tomography to investigate in humans the role of dopamine (DA) and the brain circuits it regulates in these processes. We have shown that increases in DA are associated with the subjective reports of drug reinforcement corroborating the relevance of drug-induced DA increases in the rewarding effects of drugs in humans. During withdrawal we have shown in drug abusers significant reductions in DA D2 receptors and in DA release. We postulate that this hypodopaminergic state would result in a decreased sensitivity to natural reinforcers perpetuating the use of the drug as a means to compensate for this deficit and contributing to the anhedonia and dysphoria seen during withdrawal. Because the D2 reductions are associated with decreased activity in the anterior cingulate gyrus and in the orbitofrontal cortex we postulate that this is one of the mechanisms by which DA disruption leads to compulsive drug administration and the lack of control over drug intake in the drug-addicted individual. This is supported by studies showing that during craving these frontal regions become hyperactive in proportion to the intensity of the craving. Craving is also associated with activation of memory circuits including the amygdala (implicated in conditioned learning), hippocampus (implicated in declarative learning), and dorsal striatum (implicated in habit learning) all of which receive DA innervation. We therefore postulate that dopamine contributes to addiction by disrupting the frontal cortical circuits that regulate motivation, drive, and self-control and by memory circuits that increase the motivational salience of the drug and drug-associated stimuli.     

Validity evidence of the Health-Related Quality of Life for Drug Abusers Test based on the Biaxial Model of Addiction

The aim of this work is to show evidence of the validity of the Health-Related Quality of Life for Drug Abusers Test (HRQoLDA Test). This test was developed to measure specific HRQoL for drugs abusers, within the theoretical addiction framework of the biaxial model. The sample comprised 138 patients diagnosed with opiate drug dependence. In this study, the following constructs and variables of the biaxial model were measured: severity of dependence, physical health status, psychological adjustment and substance consumption. Results indicate that the HRQoLDA Test scores are related to dependency and consumption-related problems. Multiple regression analysis reveals that HRQoL can be predicted from drug dependence, physical health status and psychological adjustment. These results contribute empirical evidence of the theoretical relationships established between HRQoL and the biaxial model, and they support the interpretation of the HRQoLDA Test to measure HRQoL in drug abusers, thus providing a test to measure this specific construct in this population.     

脑岛在成瘾中的结构和功能异常

脑岛位于大脑外侧裂的深处, 与情绪和内感受等多种心理功能有关。脑岛在成瘾中的结构变化和功能连接异常, 表明了脑岛在成瘾中的作用, 刺激脑岛区域干预成瘾也逐渐成为研究者们关注的领域。未来的研究应该通过对脑岛进行精细分割和多种方法相结合来进一步考察脑岛在成瘾中的具体作用, 并挖掘不同成瘾类型的共性和特性, 以便更好开展基于脑的成瘾干预。     

Central inhibitory dysfunctions: mechanisms and clinical implications

Injury to the central or peripheral nervous system is often associated with persistent pain. After ischemic injury to the spinal cord, rats develop severe mechanical allodynia-like symptoms, expressed as a pain-like response to innocuous stimuli. In its short-lasting phase the allodynia can be relieved with the gamma-aminobutyric acid (GABA)-B receptor agonist baclofen, which also reverses the hyperexcitability of dorsal horn interneurons to mechanical stimuli. Furthermore, there is a reduction in GABA immunoreactivity in the dorsal horn of allodynic rats. Clinical neuropathic pain of peripheral and central origin often cannot be relieved by opiates at doses that do not cause side effects. The loss of sensitivity to opiates may be associated with the up-regulation of endogenous antiopioid substances, such as the neuropeptide cholecystokinin (CCK). CCK and its receptor (CCK-R) protein is normally not detectable in rat dorsal root ganglion cells. After peripheral nerve section, both CCK and CCK-R are up-regulated in the dorsal root ganglia. Furthermore, CI 988, an antagonist of the CCK-B receptor, chronically coadministered with morphine, reduces autotomy, a behavior that may be a sign of neuropathic pain following peripheral nerve section. Thus, opiate insensitivity may be due to the release of CCK from injured primary afferents. Similarly, in the chronic phase of the spinal ischemic model of central pain, the allodynia-like symptom is not relieved by systemic morphine, but is significantly reversed by the CCK-B antagonist. Consequently, up-regulation of CCK and CCK-R in the CNS may also underlie opiate drug insensitivity following CNS injury. Thus, dysfunction of central inhibition involving GABA and endogenous opioids may be a factor underlying the development of sensory abnormalities and/or pain following injury to neural tissue.     

冲动性对不同成瘾行为发展的调控及其神经机制

近年来越来越多的研究证据提示, 个体冲动性在成瘾疾患发生发展机制中具有关键作用, 可能成为成瘾行为的潜在易感标记以及早期识别和干预的重要靶点, 但冲动性对不同成瘾行为变化发展的调控机制尚不明确。项目拟综合跨成瘾谱系比较、纵向追踪设计、冲动行为干预等研究途径, 采用人格测量、神经认知、神经影像等技术, 首先比较尼古丁依赖者与网络游戏成瘾者的冲动性结构及其在前额叶–纹状体环路的结构功能改变; 然后采用混合分组设计筛选出具有高低冲动性的非成瘾青少年进行连续追踪研究, 考察冲动性对尼古丁依赖与网络游戏成瘾的预测效力; 并采用认知行为训练, 对吸烟成瘾者与网络游戏成瘾者进行冲动干预, 考察行为干预对冲动性水平及前额叶–纹状体环路功能的改变, 以及对不同成瘾行为发展的抑制后效。旨在探索冲动性作为成瘾的潜在易感标记及干预靶点的效力。     

Biopsychology research in China

The early studies on biopsychology in China were classified under the name of physiological psychology and comparative psychology. In 1979 the Division of Physiological Psychology of the Chinese Psychological Society was founded. Fifteen years later, the Brain‐Behavior Research Center was founded at the Institute of Psychology, Chinese Academy of Sciences. The objective of the Center was to establish a multidisciplinary scientific environment for conducting experimental research on the relationship between brain and behaviour as well as the interactions of the mind and body. A wide range of studies in biopsychology has been conducted in China. The most major research areas are: (1) Behavioural and physiological studies of stress: Research work includes the effect of early environment on stressful responses, interactions of behavioural and endocrine responses under stress, effects of emotional stress on immune function, stress and hypertension and the related role of interleukin‐1. (2) Conditioning and immunity: Studies focus on the effects of conditioning in the modulation of bidirectional immune function. Data from different experiments demonstrate that psychological processes are capable of influencing immune function. The neural substrates are also explored. (3) Memory and learning: Studies mostly concentrate on types of memory formation and training stimulus, effect of light exposure and corticosterone on learning and memory, and the role of the hippocampus in learning and memory. (4) Drug addiction: Work mainly focuses on long‐term aspects of addiction, including memory, novelty seeking, motivation‐related models, and the brain mechanisms underlying morphine psychological dependence.     

中枢胆碱能系统对吗啡成瘾的影响研究现状

介绍了中枢胆碱能系统对吗啡成瘾的影响及其机制。研究结果表明,吗啡成瘾过程中伏隔核等脑区细胞间乙酰胆碱水平发生了改变;去除伏隔核等脑区胆碱能细胞强化了吗啡成瘾行为;胆碱能激动剂和抑制剂都能干预吗啡成瘾、但机制可能不同——前者可能通过与多巴胺能交互作用来实现,后者可能通过干扰记忆或者加速吗啡代谢而发挥作用;胆碱能受体对吗啡成瘾也具有重要影响     

Withdrawal from cocaine self-administration produces long-lasting deficits in orbitofrontal-dependent reversal learning in rats

Drug addicts make poor decisions. These decision-making deficits have been modeled in addicts and laboratory animals using reversal-learning tasks. However, persistent reversal-learning impairments have been shown in rats and monkeys only after noncontingent cocaine injections. Current thinking holds that to represent the human condition effectively, animal models of addiction must utilize self-administration procedures in which drug is earned contingently; thus, it remains unclear whether reversal-learning deficits caused by noncontingent cocaine exposure are relevant to addiction. To test whether reversal learning deficits are caused by contingent cocaine exposure, we trained rats to self-administer cocaine, assessed cue-induced cocaine seeking in extinction tests after 1 and 30 d of withdrawal, and then tested for reversal learning more than a month later. We found robust time-dependent increases in cue-induced cocaine seeking in the two extinction tests (incubation of craving) and severe reversal-learning impairments.     

毒扁豆碱对吗啡导致的大鼠行为敏感化的抑制作用

药物滥用导致的行为敏感化被认为与成瘾过程密切相关。本实验探讨吗啡导致的大鼠行为敏感化与神经递质乙酰胆碱的关系。实验动物分为3组,分别进行生理盐水、吗啡（10.0mg/kg）、吗啡（10.0mg/kg）＋胆碱酯酶抑制剂毒扁豆碱（0.2mg/kg）前处理,36小时腹腔注射4次。前处理结束1周所有动物注射小剂量吗啡（4.0mg/kg）;使用生理盐水前处理的动物,第2周注射毒扁豆碱（0.2mg/kg）;使用吗啡前处理的动物,第2周注射小剂量吗啡＋毒扁豆碱（0.2mg/kg）,第3周再次注射小剂量吗啡。动物每次接受注射后立即记录其在两小时内的活动量(10分钟为一个记录单元)。结果表明,毒扁豆碱既能够抑制吗啡诱导的行为敏感化,也能够阻断小剂量吗啡对行为敏感化的“点燃”作用。由此推论,吗啡导致的行为敏感化与其抑制乙酰胆碱分泌有关。