Non-addictive psychoactive drug use: Implications for behavioral addiction

The newly proposed framework for non-addictive psychoactive substances postulated by Müller & Schumann (M&S) provides an interesting and plausible explanation for non-addictive drug use. However, with specific reference to the relevant behavioral addiction literature, this commentary argues that the model may unexpectedly hold utility not only for non-addictive use of drugs, but also for non-addictive use of other potentially addictive behaviors.     

To use or not to use: Expanding the view on non-addictive psychoactive drug consumption and its implications

Proposing a change to the view on psychoactive drug use in non-addicts touches a sensitive issue because of its potential implications to addiction prevention, therapeutic practice, and drug policy. Commentators raised nine questions that ranged from clarifications, suggested extensions of the model to supporting data previously not regarded, to assumptions on the implications of the model. Here, we take up the suggestions of the commentators to expand the model to behavioral addictions, discuss additional instrumentalization goals, and review the evidence from laboratory animal studies on drug instrumentalization. We consider further the role of sociocultural factors and individual development in the establishment in drug instrumentalization and addiction. Finally, we clarify which implications we think this model may have. We conclude that drug instrumentalization theory can be further applied to other behaviors but will require a sensitive debate when used for drug and addiction policy that directly affects prevention and treatment.     

Aberrant learning and memory in addiction

Over the past several years, drug addiction has increasingly been accepted to be a disease of the brain as opposed to simply being due to a lack of willpower or personality flaw. Exposure to addictive substances has been shown to create enduring changes in brain structure and function that are thought to underlie the transition to addiction. Specific genetic and environmental vulnerability factors also influence the impact of drugs of abuse on the brain and can enhance the likelihood of becoming an addict. Long-lasting alterations in brain function have been found in neural circuits that are known to be responsible for normal appetitive learning and memory processes and it has been hypothesized that drugs of abuse enhance positive learning and memory about the drug while inhibiting learning about the negative consequences of drug use. Therefore, the addict's behavior becomes increasingly directed towards obtaining and using drugs of abuse, while at the same time developing a poorer ability to stop using, even when the drug is less rewarding or interferes with functioning in other facets of life. In this review we will discuss the clinical evidence that addicted individuals have altered learning and memory and describe the possible neural substrates of this dysfunction. In addition, we will explore the pre-clinical evidence that drugs of abuse cause a progressive disorder of learning and memory, review the molecular and neurobiological changes that may underlie this disorder, determine the genetic and environmental factors that may increase vulnerability to addiction, and suggest potential strategies for treating addiction through manipulations of learning and memory.     

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。     

Psychoactive drug use: Expand the scope of outcome assessment

The "hijacking" and "drug instrumentalization" models of psychoactive drug use predict opposite outcomes in terms of adaptive behavior and fitness benefits. Which is the range of applicability of each model? To answer this question, we need more data than those reported by studies focusing on medical, psychiatric, and legal problems in addicted users. An evolutionary analysis requires a much wider focus.     

Drug instrumentalization and evolution: Going even further

Müller & Schumann (M&S) deserve applause for their interdisciplinary examination of drug use, evolution, and learning. Further steps can deepen their evolutionary analysis: a focus on adaptive benefits, a distinction between approach and consummatory behaviors, an examination of how drugs can create adaptive lag through changing human niche construction, the importance of other neurobehavioral mechanisms in drug use besides instrumentalization, and the importance of sociocultural dynamics and neural plasticity in both human evolution and drug use.     

Toward an evolutionary basis for resilience to drug addiction

According to Müller & Schumann (M&S), people would have evolved adaptations for learning to use psychoactive plants and drugs as instruments that reveal particularly advantageous in modern urban environments. Here I "instrumentalize" this framework to propose an evolutionary basis for the existence of a biological resilience to drug addiction in people.     

大脑皮层-背侧纹状体通路在吗啡强迫性觅药和用药行为中的作用

药物成瘾是以强迫性觅药和用药行为为核心特征的慢性脑疾病。从初始用药到强迫性用药是成瘾者的觅药行为从目标导向性向习惯化发展的过程。强迫性觅药和用药行为是依赖于背外侧纹状体的习惯化行为, 同时前额叶皮层-背内侧纹状体通路对行为的控制减弱, 导致感觉运动皮层-背外侧纹状体通路对行为的控制持续占主导地位, 是成瘾行为具有强迫性特征的重要神经基础。本项目围绕这一重要问题展开研究, 在建立具有成瘾特征的动物模型的基础上, 采用行为学、行为药理学和组织形态学等方法揭示皮层-纹状体通路在强迫性觅药和用药行为中的作用。研究结果有望为进一步寻找该神经网络参与成瘾行为的分子机制提供重要线索。     

Why do we take drugs? From the drug-reinforcement theory to a novel concept of drug instrumentalization

The drug-reinforcement theory explains why humans get engaged in drug taking behavior. This theory posits that drugs of abuse serve as biological rewards by activating the reinforcement system. Although from a psychological and neurobiological perspective this theory is extremely helpful, it does not tell us about the drug-taking motives and motivation of an individual. The definition of drug instrumentalization goals will improve our understanding of individual drug-taking profiles.     

非药物成瘾的遗传学和神经生物学机制研究述评

非药物成瘾又称“非物质相关性成瘾”或“行为成瘾”。特征性表现包括对成瘾对象的渴望、受损的冲动控制、对成瘾对象的耐受、撤退反应和高复发率等。目前发现的非药物成瘾类型包括病理性赌博、网络成瘾、购物成瘾、游戏成瘾、性瘾以及贪食等。非药物成瘾与药物成瘾在症状学上表现出很高的相似性且具有较高的共病率, 提示二者之间可能存在着共同的发病机制。从遗传学和神经生物学的角度探讨非药物成瘾的机制具有重要的理论价值和临床应用价值。家庭研究和双生子研究发现, 男性的病理性赌博和贪食障碍具有中度以上的遗传度。分子遗传学研究发现, 单胺能神经递质相关基因, 如5-羟色胺转运体基因、多巴胺受体基因和单胺氧化酶A基因等, 与非药物成瘾有关。神经影像学研究发现, 非药物成瘾者脑内负责奖赏,线索加工和冲动控制的神经通路活动性异于正常对照。未来研究需要进一步从多个角度入手, 探讨非药物成瘾与药物成瘾的共性和特性。     

基于“相关线索-自动化用药行为”联结的成瘾记忆消退

成瘾记忆消退致力于消除成瘾者相关线索与药物奖赏效应的联结,以达到消除心理渴求、戒断成瘾行为的目的,但其效果还十分有限。最近,大量的动物和人类实验研究发现:在相关线索下,成瘾者的激活脑区不仅包括中脑边缘皮层-背内侧纹状体,还延伸到感觉运动脑区-背外侧纹状体。这意味着成瘾记忆中存在相关线索与自动化(习惯性)用药行为的联结。所以,与成瘾相关的记忆可能包含两种不同的成分:一是与药物奖赏效应相关的情绪记忆,另一种是与用药动作、技能有关的动作记忆(程序记忆)。由于在成瘾阶段,药物奖赏效应对药物使用和复发的作用已经相对减少,因此,针对成瘾记忆的消退训练,以相关线索与自动化用药行为的联结为标靶,可能可以取得更好的效果,值得做进一步的深入探索。     

物质成瘾及其戒除:基于反转学习的视角

物质成瘾与反转学习损伤密切相关,成瘾者往往不能灵活地适应变化的刺激—结果的联结,这可能进一步加剧成瘾者的物质使用。近年来研究发现,物质成瘾者的反转学习相关的腹外侧前额和背外侧前额等脑区激活异常,这些异常与成瘾者的冲动性和强迫性有关。此外,个体的反转学习能力对其成瘾行为具有一定预测性。今后应增加对不同类型物质成瘾者的反转学习脑机制及物质相关线索对成瘾者反转学习影响的研究,并且进一步探讨成瘾者的冲动性和强迫性对其反转学习的调节及个体反转学习能力对其成瘾行为的预测。     

Is an epigenetic switch the key to persistent extinction?

Many studies of learning have demonstrated that conditioned behavior can be eliminated when previously established relations between stimuli are severed. This extinction process has been extremely important for the development of learning theories and, more recently, for delineating the neurobiological mechanisms that underlie memory. A key finding from behavioral studies of extinction is that extinction eliminates behavior without eliminating the original memory; extinguished behavior often returns with time or with a return to the context in which the original learning occurred. This persistence of the original memory after extinction creates a challenge for clinical applications that use extinction as part of a treatment intervention. Consequently, a goal of recent neurobiological research on extinction is to identify potential pharmacological targets that may result in persistent extinction. Drugs that promote epigenetic changes are particularly promising because they can result in a long-term molecular signal that, combined with the appropriate behavioral treatment, can cause persistent changes in behavior induced by extinction. We will review evidence demonstrating extinction enhancements by drugs that target epigenetic mechanisms and will describe some of the challenges that epigenetic approaches face in promoting persistent suppression of memories.     

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。     

Caffeine effects on mood and memory.

The purpose of the present research was to assess whether a psychoactive dose of caffeine would have differential affects on the mood dimensions of arousal versus feelings of pleasantness and whether these mood alterations would influence memory either by (1) the experience of arousal at learning and/or (2) altered and congruent mood states at learning and recall. To address these questions, the administration of 5 mg/kg caffeine or placebo at learning and retrieval sessions was manipulated and subjects' mood was evaluated by several different self-report measures. Sixteen words were incidentally studied during the learning session and memory was evaluated by the number of words correctly recalled at the retrieval session two days later. Results revealed that caffeine reliably increased arousal, but did not affect any emotion dimensions related to feelings of pleasure. Subjects who received caffeine at learning and retrieval were also in equivalent mood states at both sessions. Moreover, caffeine did not produce any effects on memory; thus, neither hypothesis concerning the influence of arousal on memory was supported. These data show that caffeine is a useful method for manipulating arousal in the laboratory without influencing feelings of pleasantness or learning and memory performance.     

Drugs as instruments from a developmental child and adolescent psychiatric perspective

Developmental, epidemiological, and neurobiological studies indicate that the adaptive and maladaptive functions, as well as immediate and long-term consequences of drug use, may vary by age. Early initiation seems to be associated with a reduced ability to use drugs purposely in a temporally stable, non-addictive manner. Prevention strategies should consider social environmental factors and aim to delay age at initiation.     

Intra-amygdala anxiogenic drug infusion prior to retrieval biases rats towards the use of habit memory

In a dual-solution plus-maze task that can be acquired using either hippocampus-dependent "cognitive/place" learning or dorsal striatal-dependent "habit/response" learning, pre-acquisition peripheral or intra-basolateral amygdala (BLA) injections of anxiogenic drugs result in the predominant use of response learning. The present experiments examined the effect of anxiogenic drug treatment on the relative use of multiple memory systems when administered prior to memory retrieval. Adult male Long-Evans rats were trained for two days (6 trials/day, 30s ITI) in a dual-solution plus-maze task to swim from the same start point (south) to an escape platform that was located in a consistent goal arm (west). On day three, prior to a memory retrieval probe trial from a novel start point (north), rats received a peripheral (0.03, 0.1 or 0.3 mg/kg), or intra-BLA (0.1 microg/0.5 microl) injection of the anxiogenic alpha(2)-adrenoreceptor antagonist RS 79948-197, or saline. Relative to saline controls, rats receiving either peripheral or intra-BLA infusions of RS 79948-197 predominantly displayed response learning on the probe trial. In an additional experiment peripheral (0.1 mg/kg) or intra-BLA (0.1 microg) drug injections administered prior to both acquisition and retrieval also resulted in the predominant use of response learning. The findings indicate that (1) similar to acquisition, peripheral injection of an anxiogenic drug prior to memory retrieval biases rats towards the use of habit/response memory, (2) intra-BLA infusions of an anxiogenic drug is sufficient to produce this modulatory effect of emotional state on memory retrieval, and (3) state-dependency does not appear to play a role in the effects of anxiogenic drug treatment on multiple memory system use. The findings may have implications for understanding the interaction between brain function, emotion, and the relative use of multiple memory systems in human psychopathology.     

But is it evolution…?

We applaud Müller & Schumann (M&S) for bringing needed attention to the problem of motivation for common non-addictive drug use, as opposed to the usual focus on exotic drugs and addiction. Unfortunately, their target article has many underdeveloped and sometimes contradictory ideas. Here, we will focus on three key issues.     

Explaining Addiction: How Far Does the Reward Account of Motivation Take Us?

ABSTRACT

Choice theorists such as George Ainslie and Gene Heyman argue that the drug-seeking behaviour of addicts is best understood in the same terms that explain everyday choices. Everyday choices, they claim, aim to maximise the reward from available incentives. Continuing drug-use is, therefore, what addicts most want given the incentives they are aware of but they will change their behaviour if and when better incentives become available. This model might explain many typical cases of addiction, but there are hard cases that pose a problem. In these hard cases the addicted individual does not cease using drugs in the face of consequences that are so adverse it is implausible that they are unaware of more rewarding paths of action. These cases force the choice theorist into a dilemma: either these addicts’ drug use does not count as action and so is best described by a neurobiological model, or reference to ‘reward’ in these cases means merely ‘motivated’ and so provides no explanatory power. We propose a different model of motivation that takes self-conception into account. We show how that can better explain the hard cases of addiction and also inform our understanding of recovery and self-control.     

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。