甲基苯丙胺成瘾者情绪加工障碍的机制及其临床干预方法的整合研究进展

近年来,在中国以甲基苯丙胺为代表的合成毒品使用人数已经超过海洛因等传统毒品,而且滥用问题日益严重.情绪问题是诱发甲基苯丙胺成瘾者复吸的重要因素.慢性使用甲基苯丙胺导致前额叶-边缘单胺类神经递质系统及相应神经环路结构和功能损害,是成瘾者出现情绪加工障碍的原因.本文从情绪体验、情绪识别与表达和线索诱发的情绪反应性三个方面总结甲基苯丙胺成瘾者情绪加工障碍的表现形式,及相应神经递质系统神经环路基础.指出易激惹和愤怒攻击行为是甲基苯丙胺成瘾过程需要重点关注的情绪问题,并进一步总结了甲基苯丙胺成瘾者情绪障碍的临床治疗和干预的潜在方法,包括药物手段、神经调控技术、认知与行为治疗等,特别是信息科学和脑科学的新技术,如虚拟现实整合多感觉通道的情绪信息,并结合神经调控技术可为甲基苯丙胺成瘾者情绪加工障碍的临床干预提供新的视角.     

药物成瘾及成瘾记忆的研究现状

本文在介绍药物成瘾与学习和记忆密切相关的神经回路及共同分子机制的基础上,围绕学习和记忆在药物成瘾中的作用,综述了关联性学习与复吸,关联性学习与敏化,异常关联性学习与强迫性用药行为,关联性学习及成瘾记忆与成瘾,多重记忆系统与成瘾的发生发展等方面的研究进展,并强调了突触可塑性及成瘾记忆在药物成瘾中的重要性。在此基础上提出：作为慢性脑病的药物成瘾的形成过程的重要特征是它包含着信息的特殊学习类型。药物成瘾与依赖于多巴胺的关联性学习紊乱有密切关系。海马可能在成瘾中扮演重要角色。     

心得安对ICR小鼠吗啡诱导的条件化位置偏爱记忆获得和提取的影响

利用心得安阻断β-肾上腺素受体(β-受体),从而干扰药物成瘾患者对药物环境线索记忆的某些环节(如再巩固等),进而降低或抑制其对成瘾药物的渴求,已成为未来治疗复吸的潜在途径.但目前,心得安对吗啡相关环境线索记忆的获得及提取的影响尚不清楚.因此,该实验检测了心得安对小鼠吗啡诱导的条件化位置偏爱(conditioned place preference,CPP)环境线索记忆的获得和提取的影响.该研究首次发现在吗啡CPP记忆的获得期,心得安不影响CPP的表达和消退,提示β-受体不参与吗啡诱导CPP学习记忆的获得;而在吗啡CPP记忆的提取期,心得安可延缓CPP的消退,提示β-受体与吗啡诱导CPP学习记忆的提取相关.该结果表明,药物成瘾过程与β-受体相关,为成瘾等精神疾病的治疗提供了新的理论依据.     

条件化恐惧记忆消退的神经振荡机制

恐惧作为个体应对内外界危险因素形成的自我保护机制的一部分,在生物体的生存中发挥着重要作用.但过度的恐惧不仅对个体生存无益,反而易引发创伤后应激障碍、焦虑等精神疾病,严重影响个体生活质量.临床上通常采用基于行为学研究结果的暴露疗法对恐惧相关疾病进行治疗,然而在患者处于治疗环境之外的时候,上述症状经常会复发.因此,解析恐惧记忆相关神经环路内信息处理的神经机制,对于理解这些疾病的发生发展,寻求切实有效的治疗方案至关重要.大量研究表明与恐惧记忆消退相关的脑区主要涉及杏仁核、内侧前额叶和海马.在恐惧消退的过程中,这3个脑区表现出特定的神经振荡模式,而且这些活动也具有同步性,构成了恐惧记忆成功消退的神经基础.未来可利用基于神经神经振荡的无创性脑刺激手段干预恐惧记忆消退的神经环路,以促进恐惧记忆的消退并避免复发,为恐惧相关障碍的临床治疗提供重要的科学依据.     

非侵入性脑刺激应用于创伤后应激障碍和物质滥用障碍的记忆干预

记忆是进行思维、想象等高级心理活动的基础，是累积经验、促进个体生存的重要功能。然而，创伤后应激障碍和物质滥用障碍具有某种非适应性记忆过强的特征，不利于个体生存。因此，以病理性改变的记忆为靶点，通过削弱或更新非适应性记忆，可以达到缓解症状甚至治愈的目的。记忆并非是对经验的刻板记录，而是对经验不断更新整合的过程，因此记忆有被干预的可能。记忆的再次激活可能会诱发记忆消退和再巩固，这为记忆相关精神疾病的干预提供了思路和启发。非侵入性脑刺激（noninvasive brain stimulation,NIBS）技术作为一种时间、空间分辨率较高的无创神经调控技术，近年来开始被结合运用到记忆干预研究中。不同刺激参数的NIBS （如频率、极性，以及受刺激区域的初始神经激活状态）应用于特定大脑皮质区域，可以调节神经可塑性，增强或降低靶点脑区的兴奋性，从而削弱或增强行为表现，实现记忆消退增强或在再巩固时间窗内干预记忆。本文首先介绍了记忆相关的脑功能基础研究与局部脑区干预方案的理论联系，继而回顾了近年来NIBS与记忆干预相结合应用于创伤或物质滥用相关障碍的临床干预研究，为精神疾病临床诊疗提供理论依据和启发。     

网络成瘾的生物学机制研究与展望

网络成瘾是指由于过度使用网络而导致社会及心理损害的现象,危害极大,故受到广泛关注。网络成瘾主要受生物学机制的调控。在脑神经机制方面,通过对成瘾者的自发脑电、事件相关电位以及成瘾者静息态BOLD-f MRI的分析,发现成瘾者脑功能区出现异常。同时,网络成瘾也受到自主神经功能的影响。另外,脑内奖赏系统和成瘾记忆模型也可能成为引发网络成瘾的脑神经机制。体内化学物质的失衡也能引发网络成瘾。鉴于此,一些治疗方法如药物干预、行为干预、认知干预以及综合干预疗法使得根治网络成瘾成为可能。本文拟从网络成瘾的概念、表现特点、不良影响及其发生的生物学机制等方面的研究进展进行阐述,以期为相关研究提供一些有价值的参考依据。     

药物成瘾中不同环境线索诱发觅药行为的机制

接触药物相关环境线索可激发成瘾者对药物的渴求感及复吸行为。实验动物研究中药物相关环境线索分为三类:伴药线索、辨别线索和情境线索。在长期停药及用药行为消退后三种环境线索均能诱发觅药行为恢复,而行为机制各具特点:伴药线索条件性强化觅药行为,辨别线索直接激发觅药行为发生,情境线索设定场景诱发觅药行为恢复。三种线索行为效应的神经基础局部相同而又各具特点,其机制的研究有助于对成瘾药物复吸机制的理解及临床戒毒治疗。     

两种复吸动物模型的神经生物学机制

复吸是指撤药一段时间后,觅药和用药行为的恢复。它是药物成瘾的主要特征之一,也是药物成瘾治疗亟待解决的头号难题。本文介绍两种复吸动物模型——自身给药消退恢复模型、条件性位置偏爱消退复燃模型建立的方法,对模型的效标效度进行评价,探讨复吸的神经生物学机制,为药物成瘾的治疗提供研究思路。     

网络成瘾者奖赏系统和认知控制系统的神经机制

网络成瘾作为一种行为成瘾,已成为严重影响人们心理健康的全球性问题.根据大脑发育的神经生物模型,揭示网络成瘾者奖赏和认知控制系统的神经机制是解决网络成瘾问题的关键,也是心理学研究的重大问题.行为研究探讨了网络成瘾具有高奖赏寻求和低认知控制特征;神经机制研究揭示了奖赏和认知控制系统的缺陷是网络成瘾行为的高风险因素;与药物成瘾的比较研究发现,网络成瘾有着独特的奖赏机制.这些研究深化了对网络成瘾心理和神经机制的理解,但仍存在网络成瘾筛查和入组标准不科学、分型笼统、因果研究匮乏、干预和治疗效果具有争议、研究范式存在漏洞等一些急需解决的问题.     

伏隔核壳部巴氯芬灌注阻断吗啡成瘾小鼠条件位置性偏爱记忆再巩固

氨基丁酸B型受体(GABAB受体)是治疗药物成瘾的潜在靶点,伏隔核壳部(nucleus accumbens shell, AcbSh)是成瘾环路的关键节点,但AcbSh GABA_B受体与记忆再巩固的关系尚不清楚。本文旨在探讨AcbSh微量灌注GABA_B受体激动剂巴氯芬(baclofen, BLF)对吗啡奖赏记忆再巩固及复吸行为的影响。建立吗啡条件位置性偏爱(conditioned place preference, CPP)小鼠模型,采用吗啡奖赏记忆提取激活实验,对比观察环境线索激活吗啡奖赏记忆后,双侧AcbSh灌注BLF对吗啡CPP、吗啡激发CPP重建以及自主活动量的影响。结果表明,吗啡奖赏记忆激活后,Acb Sh单次注入0.06nmol/0.2μL/侧或0.12nmol/0.2μL/侧BLF显著抑制吗啡CPP,且吗啡激发不能重建CPP,而0.01nmol/0.2μL/侧BLF灌注不能抑制吗啡CPP。激活后注入生理盐水及未激活组BLF灌注均未抑制CPP。无论是否激活吗啡奖赏记忆,BLF注入AcbSh都不影响小鼠自主活动。以上结果提示,AcbSh GABA_B受体参与了吗啡CPP的记忆再巩固。记忆激活后激动AcbSh GABA_B受体可通过阻断吗啡CPP的记忆再巩固,消除奖赏记忆,抑制复吸行为。     

Removing pathogenic memories

Experimental research examining the neural bases of nondeclarative memory has offered intriguing insight into how functional and dysfunctional implicit learning affects the brain. Long-term modifications of synaptic transmission, in particular, are currently considered the most plausible mechanism underlying memory trace encoding and compulsions, addiction, anxiety, and phobias. Therefore, an effective psychotherapy must be directed to erase maladaptive implicit memories and aberrant synaptic plasticity. This article describes the neurobiological bases of pathogenic memory disruption to provide some insight into how psychotherapy works. At least two mechanisms of unwanted memory erasing appear to be implicated in the effects of psychotherapy: inhibition of memory consolidation/reconsolidation and extinction. Behavioral evidence demonstrated that these two ways to forget are profoundly distinct in nature, and it is increasingly clear that their cellular, synaptic, and molecular underpinnings are different. Accordingly, the blockade of consolidation/reconsolidation erases memories by reversing the plasticity associated with memory maintenance, whereas extinction is a totally new form of plasticity that, similar to the plasticity underlying the old memory, requires protein synthesis-dependent synaptic remodeling.     

Galnon Facilitates Extinction of Morphine-Conditioned Place Preference but Also Potentiates the Consolidation Process

Learning and memory systems are intimately involved in drug addiction. Previous studies suggest that galanin, a neuropeptide that binds G-protein coupled receptors, plays essential roles in the encoding of memory. In the present study, we tested the function of galnon, a galanin receptor 1 and 2 agonist, in reward-associated memory, using conditioned place preference (CPP), a widely used paradigm in drug-associated memory. Either before or following CPP-inducing morphine administration, galnon was injected at four different time points to test the effects of galanin activation on different reward-associated memory processes: 15 min before CPP training (acquisition), immediately after CPP training (consolidation), 15 min before the post-conditioning test (retrieval), and multiple injection after post-tests (reconsolidation and extinction). Galnon enhanced consolidation and extinction processes of morphine-induced CPP memory, but the compound had no effect on acquisition, retrieval, or reconsolidation processes. Our findings demonstrate that a galanin receptor 1 and 2 agonist, galnon, may be used as a viable compound to treat drug addiction by facilitating memory extinction process.     

Modeling Reconsolidation in Kernel Associative Memory

Memory reconsolidation is a central process enabling adaptive memory and the perception of a constantly changing reality. It causes memories to be strengthened, weakened or changed following their recall. A computational model of memory reconsolidation is presented. Unlike Hopfield-type memory models, our model introduces an unbounded number of attractors that are updatable and can process real-valued, large, realistic stimuli. Our model replicates three characteristic effects of the reconsolidation process on human memory: increased association, extinction of fear memories, and the ability to track and follow gradually changing objects. In addition to this behavioral validation, a continuous time version of the reconsolidation model is introduced. This version extends average rate dynamic models of brain circuits exhibiting persistent activity to include adaptivity and an unbounded number of attractors.     

Disrupting reconsolidation of drug memories reduces cocaine-seeking behavior

Maladaptive memories that associate environmental stimuli with the effects of drugs of abuse are known to be a major cause of relapse to, and persistence of, a drug addictive habit. However, memories may be disrupted after their acquisition and consolidation by impairing their reconsolidation. Here, we show that infusion of Zif268 antisense oligodeoxynucleotides into the basolateral amygdala, prior to the reactivation of a well-learned memory for a conditioned stimulus (CS)-cocaine association, abolishes the acquired conditioned reinforcing properties of the drug-associated stimulus and thus its impact on the learning of a new cocaine-seeking response. Furthermore, we show that reconsolidation of CS-fear memories also requires Zif268 in the amygdala. These results demonstrate that appetitive CS-drug memories undergo reconsolidation in a manner similar to aversive memories and that this amygdala-dependent reconsolidation can be disrupted to reduce the impact of drug cues on drug seeking.     

Effects of propranolol on acquisition and retrieval of morphine- induced conditioned place preference memories in ICR mice

To interfere with the drug-cue memory processes of addicts such as reconsolidation by the administration of the β-adrenergic receptor (β-AR) of norepinephrine (NE) antagonist propranolol (PRO) has become a potential therapy in the future to decrease or inhibit relapse. However, the relationship between PRO and the acquisition or retrieval of morphine-cue memory is not clear. This study examined the effects of PRO on the acquisition and retrieval of memories in morphine-induced conditioned place preference (CPP) mice model. We found that during memory acquisition period, PRO had no effects on the expression and extinction of morphine-CPP, which suggests that the β-AR was irrelevant to the CPP memory acquisition. However, during memory retrieval period, although PRO did not affect the expression of CPP, but it delayed the occurrence of CPP extinction, which indicates that PRO has an inhibit effect on CPP memory extinction, and β-AR plays an important role in modulating the extinction of morphine-CPP. Our study further improved the relationship between drug addiction and β-AR, and proposed a new theory to help developing potential therapy to cure addiction and other neuropsychiatric disorders.     

Linking new information to a reactivated memory requires consolidation and not reconsolidation mechanisms

A new memory is initially labile and becomes stabilized through a process of consolidation, which depends on gene expression. Stable memories, however, can again become labile if reactivated by recall and require another phase of protein synthesis in order to be maintained. This process is known as reconsolidation. The functional significance of the labile phase of reconsolidation is unknown; one hypothesis proposes that it is required to link new information with reactivated memories. Reconsolidation is distinct from the initial consolidation, and one distinction is that the requirement for specific proteins or general protein synthesis during the two processes occurs in different brain areas. Here, we identified an anatomically distinctive molecular requirement that doubly dissociates consolidation from reconsolidation of an inhibitory avoidance memory. We then used this requirement to investigate whether reconsolidation and consolidation are involved in linking new information with reactivated memories. In contrast to what the hypothesis predicted, we found that reconsolidation does not contribute to the formation of an association between new and reactivated information. Instead, it recruits mechanisms similar to those underlying consolidation of a new memory. Thus, linking new information to a reactivated memory is mediated by consolidation and not reconsolidation mechanisms.     

Cracking addiction the second time around: reconsolidation of drug-related memories

One of the greatest challenges in the understanding and treatment of addiction is cue-elicited relapse to drug use. The present findings of Miller and Marshall and Lee et al. reported in this issue of Neuron demonstrate that retrieved drug-related memories undergo reconsolidation and thus suggest that these maladaptive associations may be more labile than previously thought.