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.     

Limbic-striatal memory systems and drug addiction

Drug addiction can be understood as a pathological subversion of normal brain learning and memory processes strengthened by the motivational impact of drug-associated stimuli, leading to the establishment of compulsive drug-seeking habits. Such habits evolve through a cascade of complex associative processes with Pavlovian and instrumental components that may depend on the integration and coordination of output from several somewhat independent neural systems of learning and memory, each contributing to behavioral performance. Data are reviewed that help to define the influences of conditioned Pavlovian stimuli on goal-directed behavior via sign-tracking, motivational arousal, and conditioned reinforcement. Such influences are mediated via defined corticolimbic-striatal systems converging on the ventral striatum and driving habit-based learning that may depend on the dorsal striatum. These systems include separate and overlapping influences from the amygdala, hippocampus, and cingulate and medial prefrontal cortex on drug-seeking as well as drug-taking behavior, including the propensity to relapse.     

Neural substrates of successful working memory and long-term memory formation in a relational spatial memory task

Working memory (WM) tasks may involve brain activation actually implicated in long-term memory (LTM). In order to disentangle these two memory systems, we employed a combined WM/LTM task, using a spatial relational (object-location) memory paradigm and analyzed which brain areas were associated with successful performance for either task using fMRI. Critically, we corrected for the performance on the respective memory task when analyzing subsequent memory effects. The WM task consisted of a delayed-match-to-sample task assessed in an MRI scanner. Each trial consisted of an indoor or outdoor scene in which the exact configuration of four objects had to be remembered. After a short delay (7–13 s), the scene was presented from a different angle and spatial recognition for two objects was tested. After scanning, participants received an unexpected subsequent recognition memory (LTM) task, where the two previously unprobed objects were tested. Brain activity during encoding, delay phase and probe phase was analyzed based on WM and LTM performance. Results showed that successful WM performance, when corrected for LTM performance, was associated with greater activation in the inferior frontal gyrus and left fusiform gyrus during the early stage of the maintenance phase. A correct decision during the WM probe was accompanied by greater activation in a wide network, including bilateral hippocampus, right superior parietal gyrus and bilateral insula. No voxels exhibited supra-threshold activity during the encoding phase, and we did not find any differential activity for correct versus incorrect trials in the WM task when comparing LTM correct versus LTM incorrect trials.     

强迫性特征在药物成瘾行为中的易感性及其前额叶-反奖赏系统神经基础

强迫性是一种与不顾严重后果的固着行为密切相关的神经心理结构, 大脑神经系统对强迫性行为的调控机制崩溃是导致药物成瘾的直接原因。以往研究对于奖赏系统(中脑-皮层-边缘神经环路)在成瘾行为中的作用及机制已经具有丰富的了解, 但针对药物成瘾的强迫性特征本身以及前额叶-反奖赏系统神经环路在成瘾行为中的作用机制了解有限, 尤其是缺乏对药物成瘾强迫性特征的系统考察、缺少遗传学研究以及非兴奋剂类药物的汇聚证据。项目拟结合人类成瘾行为的遗传学视角(海洛因成瘾者与其无药物使用的兄弟姐妹对照), 结合神经认知、脑电生理、神经影像等不同层面的方法和技术, 对药物成瘾强迫性的外在表征、神经生物学基础以及与个体差异有关的遗传易感性进行探索, 期在进一步识别药物成瘾的神经生物标记, 为探寻潜在的药物或非药物干预靶点提供更多证据。     

The cellular mechanisms of memory are modified by experience

The N-methyl-D-aspartate receptor (NMDAR) is thought to be essential for synaptic plasticity and learning. However, recent work indicates that the role of this receptor depends on the prior history of the research subject. For example, animals trained on a hippocampus-dependent learning task are subsequently able to acquire new information in the absence of NMDAR activation. The current experiments were designed to identify the types of experiences that lead to NMDAR-independent learning. Using contextual fear conditioning in mice, we find that NMDAR-independent learning is only observed when (1) animals are trained on the same behavioral task and (2) initial learning is successfully encoded into long-term memory.     

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。     

Using pavlovian higher-order conditioning paradigms to investigate the neural substrates of emotional learning and memory

In first-order Pavlovian conditioning, learning is acquired by pairing a conditioned stimulus (CS) with an intrinsically motivating unconditioned stimulus (US; e.g., food or shock). In higher-order Pavlovian conditioning (sensory preconditioning and second-order conditioning), the CS is paired with a stimulus that has motivational value that is acquired rather than intrinsic. This review describes some of the ways higher-order conditioning paradigms can be used to elucidate substrates of learning and memory, primarily focusing on fear conditioning. First-order conditioning, second-order conditioning, and sensory preconditioning allow for the controlled demonstration of three distinct forms of memory, the neural substrates of which can thus be analyzed. Higher-order conditioning phenomena allow one to distinguish more precisely between processes involved in transmission of sensory or motor information and processes involved in the plasticity underlying learning. Finally, higher-order conditioning paradigms may also allow one to distinguish between processes involved in behavioral expression of memory retrieval versus processes involved in memory retrieval itself.     

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.     

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.     

Reducing mind to molecular pathways: explicating the reductionism implicit in current cellular and molecular neuroscience

As opposed to the dismissive attitude toward reductionism that is popular in current philosophy of mind, a “ruthless reductionism” is alive and thriving in “molecular and cellular cognition”—a field of research within cellular and molecular neuroscience, the current mainstream of the discipline. Basic experimental practices and emerging results from this field imply that two common assertions by philosophers and cognitive scientists are false: (1) that we do not know much about how the brain works, and (2) that lower-level neuroscience cannot explain cognition and complex behavior directly. These experimental practices involve intervening directly with molecular components of sub-cellular and gene expression pathways in neurons and then measuring specific behaviors. These behaviors are tracked using tests that are widely accepted by experimental psychologists to study the psychological phenomenon at issue (e.g., memory, attention, and perception). Here I illustrate these practices and their importance for explanation and reduction in current mainstream neuroscience by describing recent work on social recognition memory in mammals.     

ROC in animals: Uncovering the neural substrates of recollection and familiarity in episodic recognition memory

It is a consensus that familiarity and recollection contribute to episodic recognition memory. However, it remains controversial whether familiarity and recollection are qualitatively distinct processes supported by different brain regions, or whether they reflect different strengths of the same process and share the same support. In this review, I discuss how adapting standard human recognition memory paradigms to rats, performing circumscribed brain lesions and using receiver operating characteristic (ROC) methods contributed to solve this controversy. First, I describe the validation of the animal ROC paradigms and report evidence that familiarity and recollection are distinct processes in intact rats. Second, I report results from rats with hippocampal dysfunction which confirm this finding and lead to the conclusion that the hippocampus supports recollection but not familiarity. Finally, I describe a recent study focusing on the medial entorhinal cortex (MEC) that investigates the contribution of areas upstream of the hippocampus to recollection and familiarity.     

Cellular and molecular mechanisms underlying learning and memory impairments produced by cannabinoids

Why does smoking marijuana impair learning and memory? Behavioral studies suggest that a disruption of normal hippocampal function contributes to these deficits. In vitro experiments find that cannabinoid receptor activation reduces neurotransmitter release below the levels required to trigger long-term changes in synaptic strength in the hippocampus. Cannabinoids reduce glutamate release through a G-protein-mediated inhibition of the calcium channels responsible for neurotransmitter release from hippocampal neurons. These mechanisms likely play a role in the learning and memory impairments produced by cannabinoids and by endogenous cannabinoid receptor ligands.     

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。     

Pavlovian conditioning of Hermissenda: current cellular, molecular, and circuit perspectives

The less-complex central nervous system of many invertebrates make them attractive for not only the molecular analysis of the associative learning and memory, but also in determining how neural circuits are modified by learning to generate changes in behavior. The nudibranch mollusk Hermissenda crassicornis is a preparation that has contributed to an understanding of cellular and molecular mechanisms of Pavlovian conditioning. Identified neurons in the conditioned stimulus (CS) pathway have been studied in detail using biophysical, biochemical, and molecular techniques. These studies have resulted in the identification and characterization of specific membrane conductances contributing to enhanced excitability and synaptic facilitation in the CS pathway of conditioned animals. Second-messenger systems activated by the CS and US have been examined, and proteins that are regulated by one-trial and multi-trial Pavlovian conditioning have been identified in the CS pathway. The recent progress that has been made in the identification of the neural circuitry supporting the unconditioned response (UR) and conditioned response (CR) now provides for the opportunity to understand how Pavlovian conditioning is expressed in behavior.     

Extraversion and exercise addiction

Extraversion has been suggested as a factor associated with addiction. This claim was tested in relation to exercise addiction. Twelve exercise addicts were compared with 12 nonaddicted individuals who were committed to regular exercise and with 12 nonexercising individuals drawn from the same student population. Addicted exercisers did not differ from nonaddicted exercisers in extraversion, although exercisers as a group were more extraverted than nonexercisers. The results are interpreted as evidence against the claim that extraversion is a component of the addictive personality profile.