干预胆碱M受体对药物成瘾的影响及其与多巴胺的关系

药物成瘾是一类精神及行为障碍, 涉及到中枢神经系统的病变。毒蕈碱受体(Muscarinic receptor, M受体)属于胆碱能受体, 分5种亚型。行为学研究表明, 干预M受体能有效影响药物成瘾行为, 但其神经机制还亟待探索。阿片类药物与精神活性药物均能激活中枢多巴胺系统, 而M受体与多巴胺系统在多个脑区产生了交互作用。其中激动M2及M4受体抑制了多巴胺系统功能, 而激动M5受体增强了多巴胺系统功能, 与干预M2、M4、M5受体对药物成瘾行为的影响相对应。以上证据提示, 干预M受体可能通过影响多巴胺系统对药物成瘾起作用。     

药物成瘾诱导相关大脑核团功能和行为改变的DNA甲基化机制

药物成瘾会导致相关神经环路的结构和功能长期改变.大量新的研究证据表明,在DNA序列不变的情况下,药物成瘾可通过影响不同亚型DNA甲基转移酶(DNMTs)的表达,使脑内多个相关核团发生DNA甲基化以及基因表达的改变,进而导致神经元功能的可塑性变化.因此,DNA甲基化被视作导致成瘾行为长期存在的可能机制之一.结合近几年来的重要发现,本文将重点讨论相关脑区的DNA甲基化在成瘾行为发生发展过程中的作用,以及成瘾药物影响DNA甲基化水平的可能机制,并试图提出可深入的研究展望.     

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。     

成瘾相关记忆的表观遗传学机制 ——药物成瘾研究的新视角

成瘾相关记忆长期性的脑机制一直是药物成瘾研究领域的难点与热点,该文简要介绍了成瘾记忆长期性分子机制的研究脉络,提示表观遗传学修饰可能是研究药物成瘾的新视角。成瘾药物可以调节染色体不同亚型组蛋白乙酰化水平,不同基因DNA的甲基化程度从而改变染色体的空间结构,进而调节基因的表达导致成瘾,特别是DNA甲基化改变的相对的稳定性可能是成瘾记忆长期存在的分子基础。记忆再巩固过程中学习记忆相关脑区的记忆促进基因与记忆抑制基因的表观遗传学改变可能是未来研究的新趋势     

胚胎期可卡因、吗啡暴露影响子代成瘾相关行为的神经发育机制

孕期使用毒品可影响胎儿大脑的正常发育,导致脑内神经递质系统异常以及行为的改变.近年来不断有研究证据提示,胚胎期接触可卡因、吗啡等成瘾药物,可以影响神经细胞的增殖、迁移或凋亡等发育过程,使中脑皮层边缘系统中多巴胺、GABA、谷氨酸等神经元形态、受体功能以及突触可塑性发生改变,从而导致子代的学习记忆和成瘾易感性等行为异常.本文将从行为、神经发育、递质系统以及脑功能等层面归纳胚胎期用药对成瘾相关行为影响机制的重要研究进展,并试图提出可能的研究展望.     

伏隔核和中脑腹侧被盖区内食欲素在吗啡奖赏中的作用

实验采用条件性位置偏爱（CPP）模型考察中脑腹侧被盖区（VTA）和伏隔核壳区（NAcSh）内食欲素（orexin）在吗啡奖赏中的作用。Wistar大鼠分为盐水训练组和吗啡训练组。3轮吗啡（或盐水）匹配训练前,双侧VTA或NAcSh内给予OXR1拮抗剂SB334867（VTA: 0, 1, 5μg;NAcSh: 0, 1, 3μg）;或2轮吗啡（或盐水）匹配训练前NAcSh内给予orexin A（0, 2, 4, 6μg）,观察其对吗啡CPP建立的影响。结果表明,VTA内给予SB334867抑制吗啡CPP建立,并存在剂量效应关系;NAcSh内给予SB334867或orexin A均未影响吗啡CPP建立,而orexin A可增加吗啡处理大鼠的运动性。以上结果表明,VTA和NAcSh内的orexin在吗啡奖赏中扮演的角色不同,可能调控成瘾行为的不同成分     

多巴胺对动物冲动性的影响

冲动性是注意缺陷障碍、物质成瘾以及病理性赌博等常见精神疾病的主要症状, 已经成为人们日益关注的焦点。研究发现, 前额叶–纹状体神经回路多巴胺参与了冲动性的调节, 但是研究结果并不一致, 多巴胺在冲动性中发挥的作用, 可能会受到三个不同因素的影响。首先, 冲动性具有多维度特征, 多巴胺对冲动的多种亚结构的作用存在差异; 其次, 多巴胺可以通过多个脑区以及与其他递质系统的交互作用影响冲动性; 最后, 多巴胺在调节冲动性的过程中可能还受到多种变量的影响, 如个体差异、环境线索等。     

心肌缺血再灌注损伤治疗新策略——胆碱能抗炎通路

缺血再灌注损伤（ischemia／reperfusion injury,IRI）是在组织器官缺血恢复血流后,细胞代谢功能障碍及结构破坏反而加重的现象。炎症及其介质可诱发、加重心肌缺血再灌注损伤,已证明与其关系密切。胆碱能抗炎通路是新发现的一条与神经免疫机制相关的抗炎通路,通过分泌乙酰胆碱,抑制炎症因子释放,为防治心肌缺血再灌注损伤提供新的治疗策略。     

冲动性对吗啡诱导的条件性位置偏爱及行为敏感化的影响

许多研究显示, 冲动性与尼古丁、可卡因、海洛因等药物成瘾显著相关, 但它对吗啡成瘾的影响尚未见到报道。本实验考察冲动性对吗啡诱导的条件性位置偏爱及行为敏感化的影响。实验采用延迟奖赏模型将大鼠的冲动性区分为高、中、低三个水平, 每个水平设置吗啡处理组和盐水处理组。结果发现：动物对吗啡诱导的条件性位置偏爱的程度表现为低冲动组>中冲动组>高冲动组, 并且中、低冲动组动物形成了条件性位置偏爱而高冲动组没有形成这种偏爱; 在行为敏感化表达期, 与相应的盐水组比较, 高、中冲动组动物的吗啡运动激活效应显著, 而低冲动组没有达到显著水平。这些结果提示, 条件性位置偏爱任务中, 动物的冲动性越高, 吗啡的强化效应越低; 行为敏感化任务中, 动物的冲动性越高, 吗啡的运动激活效应越高。由此可见, 动物的冲动性对吗啡诱导的条件性位置偏爱及行为敏感化的影响存在差异。     

外侧缰核作用于抑郁的神经生理机制

本文旨在梳理国内外有关外侧缰核作用于抑郁神经生理机制的研究成果,以期为今后抑郁研究提供借鉴和参考。首先,阐明了外侧缰核的过度兴奋会加强对下游奖赏中心单胺能脑区的抑制从而诱发抑郁的内在通路。然后,进一步论述了介导外侧缰核过度兴奋的分子机制。最后,未来要重点以人类为被试,采用纵向设计,加强外侧缰核对抑郁的影响、作用机制及其性别差异的研究,同时考察遗传基因和环境在其间的调控效应等问题。     

Extinction training regulates neuroadaptive responses to withdrawal from chronic cocaine self-administration

Cocaine produces multiple neuroadaptations with chronic repeated use. Many of these neuroadaptations can be reversed or normalized by extinction training during withdrawal from chronic cocaine self-administration in rats. This article reviews our past and present studies on extinction-induced modulation of the neuroadaptive response to chronic cocaine in the mesolimbic dopamine system, and the role of this modulation in addictive behavior in rats. Extinction training normalizes tyrosine hydroxylase levels in the nucleus accumbens (NAc) shell, an effect that could help ameliorate dysphoria and depression associated with withdrawal from chronic cocaine use. Extinction training also increases levels of GluR1 and GluR2/3 AMPA receptor subunits, while normalizing deficits in NR1 NMDA receptor subunits, in a manner consistent with long-term potentiation of excitatory synapses in the NAc shell. Our results suggest that extinction-induced increases in AMPA and NMDA receptors may restore deficits in cortico-accumbal neurotransmission in the NAc shell and facilitate inhibitory control over cocaine-seeking behavior. Other changes identified by gene expression profiling, including up-regulation in the AMPA receptor aggregating protein Narp, suggest that extinction training induces extensive synaptic reorganization. These studies highlight potential benefits for extinction training procedures in the treatment of drug addiction.     

东莨菪碱对吗啡诱导的大鼠行为敏感化的影响

药物重复处理导致的行为敏感化与成瘾过程密切相关。本实验检验东莨菪碱对吗啡诱导的大鼠行为敏感化发展和转化的影响。实验一动物分为3组,分别进行生理盐水（对照组）、吗啡（10mg/kg,吗啡组）、吗啡（10mg/kg）＋东莨菪碱（3mg/kg,吗啡-东莨菪碱组）前处理,36小时腹腔注射4次（第1~2天）。自然戒断7天（第3~9天）。第10天,所有动物均使用吗啡（4mg/kg）激发,记录动物的自发活动量;第24天,吗啡组和吗啡-东莨菪碱组动物重复第10天的操作。实验二动物分为3组,分别接受生理盐水（对照组）、吗啡（10mg/kg,吗啡组）、吗啡（10mg/kg,吗啡-东莨菪碱组）处理,36小时腹腔注射4次（第1~3天）;间隔12小时后,3组动物分别接受生理盐水、生理盐水和东莨菪碱（3mg/kg）处理,仍为36小时腹腔注射4次（第3 ~5天）。第6~9天不进行药物处理。第10天和第17天,分别使用吗啡（4mg/kg）激发,记录动物的活动量。记录时间均为两小时(10分钟为一个记录单元)。结果表明,东莨菪碱能够抑制吗啡诱导的行为敏感化的发展,一定程度上也能够延缓行为敏感化的转化但没有阻断这种转化     

Extinction-induced neuroplasticity attenuates stress-induced cocaine seeking: a state-dependent learning hypothesis

Chronic drug use weakens excitatory neocortical input to the nucleus accumbens (NAc). We previously reported that extinction training, a form of inhibitory learning that progressively reduces cocaine-seeking behaviour when reward is withheld, reverses this deficit by up-regulating GluR1 and GluR2/3 subunits of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) glutamate receptors in the NAc. The level of GluR1 up-regulation is positively associated with a reduction in cocaine seeking, suggesting that extinction-induced up-regulation in AMPA receptors in the NAc opposes motivational influences that maintain cocaine seeking. This hypothesis is supported by the finding that over-expression of GluR1 and GluR2 in the NAc facilitates extinction of cocaine self-administration. Furthermore, a single extinction training session conducted during GluR1 and GluR2 over-expression strongly and selectively attenuates the ability of an environmental stressor to trigger relapse to cocaine seeking long after GluR1 and GluR2 over-expression declines. These results could suggest that excitatory input to the NAc promotes extinction learning, but only when memory is recalled under stressful situations. Recent studies indicate that both environmental stress and the frustrative stress of withholding reward during extinction of drug self-administration induce similar neurochemical events in the NAc. These neurochemical events could impose a "state-dependency" on extinction learning such that subsequent exposure to stress acts as a cue to enhance retrieval of extinction memory. Our results suggest that extinction-induced up-regulation in NAc AMPA receptors acts reciprocally to facilitate state-dependent extinction learning, as stressful situations evoke extinction memories that exert powerful inhibitory control over drug-seeking behaviour. These results may have important therapeutic implications for behaviour-based approaches aimed at treating drug addiction.     

Deficit in selective and divided attention associated with cholinergic basal forebrain immunotoxic lesion produced by 192-saporin; motoric/sensory deficit associated with Purkinje cell immunotoxic lesion produced by OX7-saporin

The immunotoxin 192-saporin, infused intracerebroventricularly into rats, destroys cholinergic neurons in the basal forebrain nuclei. Doses required for complete cholinergic loss also kill some Purkinje cells. The immunotoxin OX7-saporin, when infused intraventricularly into rats, destroys Purkinje cells in a pattern similar to that produced by 192-saporin, without affecting cholinergic neurons. Thus, we used OX7-saporin to distinguish behavioral effects of 192-saporin due to cerebellar damage versus those due to cholinergic cell loss. Three doses of 192-saporin (1.6, 2.6, and 3.3 micrograms/rat) were chosen along with a dose of OX7-saporin (2.0 micrograms/rat) that produced Purkinje loss equivalent to the two highest doses of 192-saporin. Groups of Fischer-344 rats were trained in the multiple choice reaction time task and retested with more complex tasks after lesioning. They were also tested in the water maze, passive avoidance, acoustic startle, and open field. The OX7-saporin group exhibited changes in many tests suggesting hypermotility and sensory deficits. The 192-saporin groups differed from the OX7-saporin group when they displayed deficits in multiple choice reaction time tasks in which novel challenges were introduced, including sessions with a noise distractor, shortened and lengthened intertrial intervals, and use of nine instead of five sources of light stimulus. The 192-saporin groups showed no impairment in the other tasks. The cholinergic basal forebrain lesion may mask some of the effects of cerebellar damage up to a threshold after which effects of Purkinje cell loss predominate when 192-saporin is administered intraventricularly.     

Glucose and physostigmine effects on morphine- and amphetamine-induced increases in locomotor activity in mice

Recent findings indicate that glucose antagonizes several behavioral effects of cholinergic antagonists and augments those of cholinergic agonists. For example, scopolamine elicits increased locomotor activity, an action which is attenuated by glucose and by combined treatment with glucose and physostigmine at doses which are individually without effect. Opiate and catecholamine agonists, such as morphine and amphetamine, also elicit hyperactivity. The present study examined interactions of glucose and physostigmine with morphine- and amphetamine-induced hyperactivity. Mice received saline, morphine (10 mg/kg), or amphetamine (1 mg/kg) 50 min prior to testing, followed by saline, physostigmine (0.01, 0.05, 0.1, or 0.2 mg/kg), or glucose (10, 50, 100, or 500 mg/kg) administered 20 min prior to activity testing in an open field. Physostigmine significantly attenuated both morphine- and amphetamine-induced increases in activity, but higher doses were required to attenuate the effects of amphetamine. Like physostigmine, glucose significantly attenuated morphine-induced activity levels, but unlike physostigmine, glucose did not attenuate amphetamine-induced activity. Thus, the behavioral effects of morphine were more susceptible to modification by physostigmine and glucose than were the effects of amphetamine. The attenuation of morphine-induced hyperactivity demonstrates a similarity between glucose and cholinergic agonists, and also indicates that glucose may inhibit, directly or indirectly, opiate functions. More generally, these findings add to the evidence that circulating glucose levels selectively influence a growing list of behavioral and neurobiological functions.     

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。     

Role of the striatal cholinergic system in the regulation of learned manipulation in rats

The experiments were performed on adult Wistar male rats trained to push with the forepaw on a fixed piston inside a narrow tube. It was found that after localized intracerebral injection of a cholinergic antagonist into the dorso-lateral (but not medial) neostriatum (i.e., the caudato-putamen) the behavioral performance requiring brief innate movements remained unchanged, but the performance requiring a prolonged pushing movement (> 50 msec) became disrupted. Microinjection of carbacholine (0.03-3 μ g/1 μ1) did not affect the performance of the acquired movements, whereas scopolamine (3 μ g/1 μ1) led to the significant decrease in pushing time. We conclude that changes in the state of the dorso-lateral neostriatal cholinergic system result only in disturbances of the sensory-controlled component of a complex instrumental movement. The 1994 Pavlovian Society Young Investigator Awardee was Nadezda Dubrovskaya, first author of this paper, which was presented at the annual meeting of the Pavlovian Society, July 3, 1994, in Prague, Czech Republic.     

Cellular mechanisms underlying neuronal excitability during morphine withdrawal in physical dependence: lessons from the magnocellular oxytocin system

Opiates are used clinically as analgesics, but their euphoric actions can lead to continued use and to dependence and addiction. While there are many factors involved in drug abuse, avoidance of stressful withdrawal symptoms is a key feature of addiction and its treatment. Fundamental to this is the need to understand the cellular processes that induce dependence and lead to the withdrawal syndrome. Many neurones in the brain express opioid receptors but only a few types of neurone develop dependence during chronic morphine exposure. The physiology of opiate-dependent cells is altered such that they require the continued presence of the drug to function normally and this is revealed, in cells that are inhibited by initial acute exposure to opiate, by a rebound hyperexcitation upon opiate withdrawal. Hypothalamic oxytocin neurones robustly develop morphine dependence and provide an exceptional opportunity to probe the cellular mechanisms underlying morphine dependence and withdrawal excitation. Although expression of morphine withdrawal excitation by oxytocin cells requires afferent inputs, the underlying mechanisms appear to reside within the oxytocin neurones themselves and probably involve changes in the intrinsic membrane properties of these neurones.