Perspectives on current directions in the neurobiology of addiction disorders relevant to genetic risk factors

There is a significant heritability of drug addiction disorders, but potential genes that may underlie such vulnerability have not been clearly identified. Common neurobiological candidates for drug abuse include genes related to dopamine, opioid neuropeptide, and glutamate transmission that play important roles in drug reward and inhibitory control. This article provides an overview of genetic polymorphisms linked to these neurobiological systems, particularly in relation to psychostimulant- and opioid-addiction vulnerability.     

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。     

Behavioral perspectives on the neuroscience of drug addiction

Neuroscientific approaches to drug addiction traditionally have been based on the premise that addiction is a process that results from brain changes that in turn result from chronic administration of drugs of abuse. An alternative approach views drug addiction as a behavioral disorder in which drugs function as preeminent reinforcers. Although there is a fundamental discrepancy between these two approaches, the emerging neuroscience of reinforcement and choice behavior eventually may shed light on the brain mechanisms involved in excessive drug use. Behavioral scientists could assist in this understanding by devoting more attention to the assessment of differences in the reinforcing strength of drugs and by attempting to develop and validate behavioral models of addiction.     

Post-training amphetamine administration enhances memory consolidation in appetitive Pavlovian conditioning: Implications for drug addiction

It has been suggested that some of the addictive potential of psychostimulant drugs of abuse such as amphetamine may result from their ability to enhance memory for drug-related experiences through actions on memory consolidation. This experiment examined whether amphetamine can specifically enhance consolidation of memory for a Pavlovian association between a neutral conditioned stimulus (CS-a light) and a rewarding unconditioned stimulus (US-food), as Pavlovian conditioning of this sort plays a major role in drug addiction. Male Long-Evans rats were given six training sessions consisting of 8 CS presentations followed by delivery of the food into a recessed food cup. After the 1st, 3rd, and 5th session, rats received subcutaneous injections of amphetamine (1.0 or 2.0 mg/kg) or saline vehicle immediately following training. Conditioned responding was assessed using the percentage of time rats spent in the food cup during the CS relative to a pre-CS baseline period. Both amphetamine-treated groups showed significantly more selective conditioned responding than saline controls. In a control experiment, there were no differences among groups given saline, 1.0 or 2.0 mg/kg amphetamine 2 h post-training, suggesting that immediate post-training amphetamine enhanced performance specifically through actions on memory consolidation rather than through non-mnemonic processes. This procedure modeled Pavlovian learning involved in drug addiction, in which the emotional valence of a drug reward is transferred to neutral drug-predictive stimuli such as drug paraphernalia. These data suggest that amphetamine may contribute to its addictive potential through actions specifically on memory consolidation.     

Drugs as instruments: a new framework for non-addictive psychoactive drug use

Most people who are regular consumers of psychoactive drugs are not drug addicts, nor will they ever become addicts. In neurobiological theories, non-addictive drug consumption is acknowledged only as a "necessary" prerequisite for addiction, but not as a stable and widespread behavior in its own right. This target article proposes a new neurobiological framework theory for non-addictive psychoactive drug consumption, introducing the concept of "drug instrumentalization." Psychoactive drugs are consumed for their effects on mental states. Humans are able to learn that mental states can be changed on purpose by drugs, in order to facilitate other, non-drug-related behaviors. We discuss specific "instrumentalization goals" and outline neurobiological mechanisms of how major classes of psychoactive drugs change mental states and serve non-drug-related behaviors. We argue that drug instrumentalization behavior may provide a functional adaptation to modern environments based on a historical selection for learning mechanisms that allow the dynamic modification of consummatory behavior. It is assumed that in order to effectively instrumentalize psychoactive drugs, the establishment of and retrieval from a drug memory is required. Here, we propose a new classification of different drug memory subtypes and discuss how they interact during drug instrumentalization learning and retrieval. Understanding the everyday utility and the learning mechanisms of non-addictive psychotropic drug use may help to prevent abuse and the transition to drug addiction in the future.     

Effects of chronic cocaine administration on spatial learning and hippocampal spine density in two genetically different strains of rats

Lewis and Fischer-344 rats have been proposed as an addiction model because of their differences in addiction behaviour. It has been suggested that drug addiction is related to learning and memory processes and depends on individual genetic background. We have evaluated learning performance using the eight-arm radial maze (RAM) in Lewis and Fischer-344 adult rats undergoing a chronic treatment with cocaine. In order to study whether morphological alterations were involved in the possible changes in learning after chronic cocaine treatment, we counted the spine density in hippocampal CA1 neurons from animals after the RAM protocol. Our results showed that Fischer-344 rats significantly took more time to carry out test acquisition and made a greater number of errors than Lewis animals. Nevertheless, cocaine treatment did not induce changes in learning and memory processes in both strains of rats. These facts indicate that there are genetic differences in spatial learning and memory that are not modified by the chronic treatment with cocaine. Moreover, hippocampal spine density is cocaine-modulated in both strains of rats. In conclusion, cocaine induces similar changes in hippocampal neurons morphology that are not related to genetic differences in spatial learning in the RAM protocol used here.     

Acetylcholine modulation of neural systems involved in learning and memory

Extensive evidence supports the view that cholinergic mechanisms modulate learning and memory formation. This paper reviews evidence for cholinergic regulation of multiple memory systems, noting that manipulations of cholinergic functions in many neural systems can enhance or impair memory for tasks generally associated with those neural systems. While parallel memory systems can be identified by combining lesions with carefully crafted tasks, most—if not all—tasks require the combinatorial participation of multiple neural systems. This paper offers the hypothesis that the magnitude of acetylcholine (ACh) release in different neural systems may regulate the relative contributions of these systems to learning. Recent studies of ACh release, obtained with in vivo microdialysis samples during training, together with direct injections of cholinergic drugs into different neural systems, provide evidence that release of ACh is important in engaging these systems during learning, and that the extent to which the systems are engaged is associated with individual differences in learning and memory.     

Interaction of the Dopaminergic System With Mechanisms of Associative Learning and Cognition:Implications for Drug Abuse

The possible role of mechanisms of associative learning in drug abuse and addiction is considered with respect to psychomotor stimulant drugs such as cocaine and amphetamine. Although the initial sites of the reinforcing effects of these drugs are associated with the mesolimbic dopamine projection to the nucleus accumbens, other important neuromodulatory influences are identified. These include the amygdala, which appears to mediate the associative processes by which environmental stimuli come to control drug-seeking behavior. Possible parallel mechanisms by which stimulant drugs enhance effects of aversive as well as rewarding stimuli are discussed. The importance of attribution and context in determining relative rewarding and aversive effects is pointed out. These attributional and contextual factors may be a function of cortical regions that may themselves be impaired by chronic drug abuse, leading to further dysexecutive control over cognition and behavior.     

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.     

The Neuropsychology of Amphetamine and Opiate Dependence: Implications for Treatment

Chronic use of amphetamines and/or opiates has been associated with a wide range of cognitive deficits, involving domains of attention, inhibitory control, planning, decision-making, learning and memory. Although both amphetamine and opiate users show marked impairment in various aspects of cognitive function, the impairment profile is distinctly different according to the substance of abuse. In light of evidence showing that cognitive impairment in drug users has a negative impact on treatment engagement and efficacy, we review substance-specific deficits on executive and memory function, and discuss possibilities to address these during treatment intervention.     

基于门户理论视角下的青少年物质成瘾

青少年物质成瘾行为受到普遍的关注, 成瘾物质滥用的机制一直是学者们探讨和研究的焦点。门户理论提出青少年发展成严重药物滥用者的过程存在顺序和阶段特征, 合法物质的使用会增加发展为非法药物使用的风险, 这种顺序效应得到了实证研究的支持。本研究在综述以往研究的基础上发现, 基于门户理论视角下青少年药物使用存在顺序效应, 但以往研究仍然存在一些不足, 例如药物使用顺序的不固定, 解释范围有限, 内在机制不清楚以及各种影响因素缺乏整合等。未来可以扩展研究对象和范围, 以深入研究顺序效应的内在机制。     

Neurobiological models of attention-deficit/hyperactivity disorder: a brief review of the empirical evidence

Attention-deficit/hyperactivity disorder (ADHD) is a psychiatric disorder characterized by inattention, impulsivity, and overactivity that begins in childhood. While considerable research has focused on the neurobiological substrates of this disorder, the specific nature of the brain dysfunction in ADHD has remained elusive. However, early data from pharmacological treatment studies, as well as from basic research in animals and humans, initially led several investigators to develop neurobiological models of ADHD. These models of ADHD and more recent evidence from neuropsychological, neuroimaging, neurochemical, and genetic research are briefly reviewed. While not completely consistent, the empirical data suggest that dysfunction in prefrontal-striatal neural circuits, as well as in brain stem catecholamine systems that innervate these circuits, may underlie the executive function deficits in ADHD.     

The role of the basal ganglia in learning and memory: insight from Parkinson's disease

It has long been known that memory is not a single process. Rather, there are different kinds of memory that are supported by distinct neural systems. This idea stemmed from early findings of dissociable patterns of memory impairments in patients with selective damage to different brain regions. These studies highlighted the role of the basal ganglia in non-declarative memory, such as procedural or habit learning, contrasting it with the known role of the medial temporal lobes in declarative memory. In recent years, major advances across multiple areas of neuroscience have revealed an important role for the basal ganglia in motivation and decision making. These findings have led to new discoveries about the role of the basal ganglia in learning and highlighted the essential role of dopamine in specific forms of learning. Here we review these recent advances with an emphasis on novel discoveries from studies of learning in patients with Parkinson's disease. We discuss how these findings promote the development of current theories away from accounts that emphasize the verbalizability of the contents of memory and towards a focus on the specific computations carried out by distinct brain regions. Finally, we discuss new challenges that arise in the face of accumulating evidence for dynamic and interconnected memory systems that jointly contribute to learning.     

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。     

Neuroimaging the sleeping brain: Insight on memory functioning in infants and toddlers

Episodic memory, or the ability to remember past events with specific detail, is central to the human experience and is related to learning and adaptive functioning in a variety of domains. In typically developing children, episodic memory emerges during infancy and improves during early childhood and beyond. Developmental processes within the hippocampus are hypothesized to be primarily responsible for both the early emergence and persistence of episodic memory in late infancy and early childhood. However, these hypotheses are based on non-human models. In-vivo investigations in early human development of hippocampal processes have been significantly limited by methodological challenges in acquiring neuroimaging data, particularly task-related functional neuroimaging data, from infants and toddlers. Recent studies in adults have shown neural activity in the brain regions supporting episodic memory during slow-wave sleep using functional magnetic resonance imaging (fMRI), and fMRI has been increasingly utilized in infancy and early childhood to address other research questions. We review initial evidence and present preliminary data showing the promise of this approach for examining hippocampal contribution to how infants and toddlers remember individual events, and their association with information about the context in which the event occurred. Overall, our review, integrated with the presentation of some preliminary data provides insight on leveraging sleep to gain new perspectives on early memory functioning.     

人类记忆再巩固研究现状及临床应用

巩固的记忆被提取后,进入不稳定状态,再重新稳定下来,这个过程称为记忆再巩固。本文首先阐述人类记忆再巩固主要研究方法和经典范式,梳理记忆再巩固在人类恐惧记忆和情景记忆两个方面的相关研究,并从认知神经科学角度整理记忆再巩固的加工机制。然后总结记忆再巩固应用于创伤性应激障碍和药物成瘾等心理障碍临床治疗的相关文献。最后本文提出未来研究的方向和建议,希冀对人类记忆再巩固的理论研究和临床应用提供新思路。