Impulsivity, compulsivity, and top-down cognitive control

Impulsivity is the tendency to act prematurely without foresight. Behavioral and neurobiological analysis of this construct, with evidence from both animal and human studies, defines several dissociable forms depending on distinct cortico-striatal substrates. One form of impulsivity depends on the temporal discounting of reward, another on motor or response disinhibition. Impulsivity is commonly associated with addiction to drugs from different pharmacological classes, but its causal role in human addiction is unclear. We characterize in neurobehavioral and neurochemical terms a rodent model of impulsivity based on premature responding in an attentional task. Evidence is surveyed that high impulsivity on this task precedes the escalation subsequently of cocaine self-administration behavior, and also a tendency toward compulsive cocaine-seeking and to relapse. These results indicate that the vulnerability to stimulant addiction may depend on an impulsivity endophenotype. Implications of these findings for the etiology, development, and treatment of drug addiction are considered.     

In search of predictive endophenotypes in addiction: insights from preclinical research

Drug addiction is widely recognized to afflict some but not all individuals by virtue of underlying risk markers and traits involving multifaceted interactions between polygenic and external factors. Remarkably, only a small proportion of individuals exposed to licit and illicit drugs develop compulsive drug‐seeking behavior, maintained in the face of adverse consequences and associated detrimental patterns of drug intake involving extended and repeated bouts of binge intoxication, withdrawal and relapse. As a consequence, research has increasingly endeavored to identify distinctive neurobehavioral mechanisms and endophenotypes that predispose individuals to compulsive drug use. However, research in active drug users is hampered by the difficulty in categorizing putatively causal behavioral traits prior to the initiation of drug use. By contrast, research in experimental animals is often hindered by the validity of approaches used to investigate the neural and psychological mechanisms of compulsive drug‐seeking habits in humans. Herein, we survey and discuss the principal findings emanating from preclinical animal research on addiction and highlight how specific behavioral endophenotypes of presumed genetic origin (e.g. trait anxiety, novelty preference and impulsivity) differentially contribute to compulsive forms of drug seeking and taking and, in particular, how these differentiate between different classes of stimulant and non‐stimulant drugs of abuse.     

单细胞转录组测序在药物成瘾研究中的应用

药物成瘾是复杂的中枢神经系统疾病，相关基础与临床研究均证实药物成瘾的神经机制及神经环路在成瘾行为形成的不同阶段逐渐发生改变。利用全基因组关联研究、全基因组测序、全外显子测序或高通量转录组测序等技术的组学研究对包括药物成瘾在内的精神疾病遗传的脆弱性进行了深入研究。上述单核苷酸多态性检测技术或测序技术主要预测疾病的遗传风险位点。然而，许多中枢神经系统疾病的发生与环境因素密切相关，而且在疾病发展的不同阶段，相关基因的表达存在脑区特异性的细胞异质性信息。因此，传统研究对发病机制的解释存在一定的局限性。单细胞转录组测序技术是针对单个细胞进行转录水平的测定，规避了传统测序对细胞群体平均转录水平检测的缺点，可以定量描述细胞异质性。近年来，单细胞转录测序技术在神经精神科学研究中的应用逐渐受到关注，本文总结了该技术在神经科学研究中的重要应用，并以药物成瘾为例，重点阐述说明其在中枢神经系统疾病中的应用价值。     

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。     

Progesterone attenuates impulsive action in a Go/No-Go task for sucrose pellets in female and male rats

Impulsivity, or a tendency to act without anticipation of future consequences, is associated with drug abuse. Impulsivity is typically separated into two main measures, impulsive action and impulsive choice. Given the association of impulsivity and drug abuse, treatments that reduce impulsivity have been proposed as an effective method for countering drug addiction. Progesterone has emerged as a promising treatment, as it is associated with decreased addiction-related behaviors and impulsive action. The goal of the present study was to determine the effects of progesterone (PRO) on impulsive action for food: a Go/No-Go task. Female and male rats responded for sucrose pellets during a Go component when lever pressing was reinforced on a variable-interval 30-s schedule. During the alternate No-Go component, withholding a lever press was reinforced on a differential reinforcement of other (DRO) behavior 30-s schedule, where a lever press reset the DRO timer. Impulsive action was operationally defined as the inability to withhold a response during the No-Go component (i.e. the number of DRO resets). Once Go/No-Go behavior was stable, responding between rats treated with PRO (0.5 mg/kg) or vehicle was examined. Progesterone significantly decreased the total number of DRO resets in both males and females, but it did not affect VI responding for sucrose pellets. This suggests that PRO decreases motor impulsivity for sucrose pellets without affecting motivation for food. Thus, PRO may reduce motor impulsivity, a behavior underlying drug addiction.     

Deletion of alpha-synuclein decreases impulsivity in mice

The presynaptic protein alpha-synuclein, associated with Parkinson's Disease (PD), plays a role in dopaminergic neurotransmission and is implicated in impulse control disorders (ICDs) such as drug addiction. In this study we investigated a potential causal relationship between alpha-synuclein and impulsivity, by evaluating differences in motor impulsivity in the 5-choice serial reaction time task (5-CSRTT) in strains of mice that differ in the expression of the alpha-synuclein gene. C57BL/6JOlaHsd mice differ from their C57BL/6J ancestors in possessing a chromosomal deletion resulting in the loss of two genes, snca, encoding alpha-synuclein, and mmrn1, encoding multimerin-1. C57BL/6J mice displayed higher impulsivity (more premature responding) than C57BL/6JOlaHsd mice when the pre-stimulus waiting interval was increased in the 5-CSRTT. In order to ensure that the reduced impulsivity was indeed related to snca, and not adjacent gene deletion, wild type (WT) and mice with targeted deletion of alpha-synuclein (KO) were tested in the 5-CSRTT. Similarly, WT mice were more impulsive than mice with targeted deletion of alpha-synuclein. Interrogation of our ongoing analysis of impulsivity in BXD recombinant inbred mouse lines revealed an association of impulsive responding with levels of alpha-synuclein expression in hippocampus. Expression of beta- and gamma-synuclein, members of the synuclein family that may substitute for alpha-synuclein following its deletion, revealed no differential compensations among the mouse strains. These findings suggest that alpha-synuclein may contribute to impulsivity and potentially, to ICDs which arise in some PD patients treated with dopaminergic medication.     

Associations between diurnal preference,impulsivity and substance use in a young-adult student sample

ABSTRACT

A diurnal preference for eveningness is common in young adulthood and previous research has associated eveningness with anxiety symptoms as well as increased smoking and alcohol use behaviors. There is some evidence that impulsivity might be an important explanatory variable in these associations, but this has not been comprehensively researched. Here we used both subjective and objective measures of impulsivity to characterize impulsive tendencies in young adults and investigated whether trait impulsivity or trait anxiety could mediate the link between eveningness and substance use. A total of 191 university students (169 females), age range 18–25 y, completed the study. Diurnal preference, sleep quality, anxiety, impulsivity, and substance use were assessed by questionnaire. Impulsivity was also measured using a delay discounting task. Eveningness correlated with trait anxiety and trait impulsivity, and these associations were still significant after controlling for sleep quality. On the delayed discounting task, eveningness correlated with a tendency to prefer smaller immediate rewards over delayed, larger ones. Evening types also reported higher levels of alcohol and cigarette use even after controlling for sleep quality. These associations were found to be completely mediated by self-reported impulsivity; anxiety did not contribute. The current results could help inform interventions aiming to reduce substance use in young adult populations.     

Review. Neural mechanisms underlying the vulnerability to develop compulsive drug-seeking habits and addiction

We hypothesize that drug addiction can be viewed as the endpoint of a series of transitions from initial voluntary drug use through the loss of control over this behaviour, such that it becomes habitual and ultimately compulsive. We describe evidence that the switch from controlled to compulsive drug seeking represents a transition at the neural level from prefrontal cortical to striatal control over drug-seeking and drug-taking behaviours as well as a progression from ventral to more dorsal domains of the striatum, mediated by its serially interconnecting dopaminergic circuitry. These neural transitions depend upon the neuroplasticity induced by chronic self-administration of drugs in both cortical and striatal structures, including long-lasting changes that are the consequence of toxic drug effects. We further summarize evidence showing that impulsivity, a spontaneously occurring behavioural tendency in outbred rats that is associated with low dopamine D2/3 receptors in the nucleus accumbens, predicts both the propensity to escalate cocaine intake and the switch to compulsive drug seeking and addiction.     

Epigenetic mechanisms in drug addiction

Changes in gene expression in brain reward regions are thought to contribute to the pathogenesis and persistence of drug addiction. Recent studies have begun to focus on the molecular mechanisms by which drugs of abuse and related environmental stimuli, such as drug-associated cues or stress, converge on the genome to alter specific gene programs. Increasing evidence suggests that these stable gene expression changes in neurons are mediated in part by epigenetic mechanisms that alter chromatin structure on specific gene promoters. This review discusses recent findings from behavioral, molecular and bioinformatic approaches being used to understand the complex epigenetic regulation of gene expression by drugs of abuse. This novel mechanistic insight might open new avenues for improved treatments of drug addiction.     

药物成瘾的神经生物学机制研究

药物滥用既是全球普遍存在的公共卫生问题,又是危害严重的社会问题。药物成瘾的本质是一种以药物引起的基因表达和神经突触可塑性改变为基础的病理性记忆。主要介绍国内外近年的重要研究成果。     

Behavioral and neuronal interactions between exercise and alcohol: Sex and genetic differences

Alcohol use disorders (AUDs) lead to early death and many devastating consequences for individuals, families and society. Currently, few effective treatments are available, but emerging research suggests exercise might be beneficial in some individuals. To develop the most effective exercise treatment program, more research on intensity, type, timing, stage of addiction, drug involved, sex of subject and subject population is needed. This review highlights the complexity of the interaction between alcohol behaviors and exercise, with a focus on the role of sex and genetics. Moreover, we describe a variety of rodent models used to investigate the neuronal physiology changes that underlie alcohol consumption and exercise. Specifically, current data indicate that moderate exercise may ameliorate neuronal damage caused by alcohol consumption. Additionally, we describe studies of rodent models in the context of hedonic substitution to draw broad conclusions about shared underlying neurobiological mechanisms. Until recently, most studies in rodents were performed only in males, and few studies have utilized different genetic strains of mice or rats. Comparing similar behavioral paradigms across sex and strain, it has become clear that major sex and genetic differences exist for each behavioral context alone (alcohol consumption and exercise) and combined. Therefore, future research in this area should be developed with careful study design and attention to address both of these factors.     

Neonatal animal models of opiate withdrawal

The symptoms of opiate withdrawal in infants are defined as neonatal abstinence syndrome (NAS). NAS is a significant cause of morbidity in term and preterm infants. Factors, such as polysubstance abuse, inadequate prenatal care, nutritional deprivation, and the biology of the developing central nervous system contribute to the challenge of evaluating and treating opiate-induced alterations in the newborn. Although research on the effects of opiates in neonatal animal models is limited, the data from adult animal models have greatly contributed to understanding and treating opiate tolerance, addiction, and withdrawal in adult humans. Yet the limited neonatal data that are available indicate that the mechanisms involved in these processes in the newborn differ from those in adult animals, and that neonatal models of opiate withdrawal are needed to understand and develop effective treatment regimens for NAS. In this review, the behavioral and neurochemical evidence from the literature is presented and suggests that mechanisms responsible for opiate tolerance, dependence, and withdrawal differ between adult and neonatal models. Also reviewed are studies that have used neonatal rodent models, the authors' preliminary data based on the use of neonatal rat and mouse models of opiate withdrawal, and other neonatal models that have been proposed for the study of neonatal opiate withdrawal.     

Temperament and Impulsivity Predictors of Smoking Cessation Outcomes

Aims

Temperament and impulsivity are powerful predictors of addiction treatment outcomes. However, a comprehensive assessment of these features has not been examined in relation to smoking cessation outcomes.

Methods

Naturalistic prospective study. Treatment-seeking smokers (n = 140) were recruited as they engaged in an occupational health clinic providing smoking cessation treatment between 2009 and 2013. Participants were assessed at baseline with measures of temperament (Temperament and Character Inventory), trait impulsivity (Barratt Impulsivity Scale), and cognitive impulsivity (Go/No Go, Delay Discounting and Iowa Gambling Task). The outcome measure was treatment status, coded as “dropout” versus “relapse” versus “abstinence” at 3, 6, and 12 months endpoints. Participants were telephonically contacted and reminded of follow-up face to face assessments at each endpoint. The participants that failed to answer the phone calls or self-reported discontinuation of treatment and failed to attend the upcoming follow-up session were coded as dropouts. The participants that self-reported continuing treatment, and successfully attended the upcoming follow-up session were coded as either “relapse” or “abstinence”, based on the results of smoking behavior self-reports cross-validated with co-oximetry hemoglobin levels. Multinomial regression models were conducted to test whether temperament and impulsivity measures predicted dropout and relapse relative to abstinence outcomes.

Results

Higher scores on temperament dimensions of novelty seeking and reward dependence predicted poorer retention across endpoints, whereas only higher scores on persistence predicted greater relapse. Higher scores on the trait dimension of non-planning impulsivity but not performance on cognitive impulsivity predicted poorer retention. Higher non-planning impulsivity and poorer performance in the Iowa Gambling Task predicted greater relapse at 3 and 6 months and 6 months respectively.

Conclusion

Temperament measures, and specifically novelty seeking and reward dependence, predict smoking cessation treatment retention, whereas persistence, non-planning impulsivity and poor decision-making predict smoking relapse.     

Genes and Pathways Co-associated with the Exposure to Multiple Drugs of Abuse,Including Alcohol,Amphetamine/Methamphetamine,Cocaine, Marijuana,Morphine, and/or Nicotine: a Review of Proteomics Analyses

Drug addiction is a chronic neuronal disease. In recent years, proteomics technology has been widely used to assess the protein expression in the brain tissues of both animals and humans exposed to addictive drugs. Through this approach, a large number of proteins potentially involved in the etiology of drug addictions have been identified, which provide a valuable resource to study protein function, biochemical pathways, and networks related to the molecular mechanisms underlying drug dependence. In this article, we summarize the recent application of proteomics to profiling protein expression patterns in animal or human brain tissues after the administration of alcohol, amphetamine/methamphetamine, cocaine, marijuana, morphine/heroin/butorphanol, or nicotine. From available reports, we compiled a list of 497 proteins associated with exposure to one or more addictive drugs, with 160 being related to exposure to at least two abused drugs. A number of biochemical pathways and biological processes appear to be enriched among these proteins, including synaptic transmission and signaling pathways related to neuronal functions. The data included in this work provide a summary and extension of the proteomics studies on drug addiction. Furthermore, the proteins and biological processes highlighted here may provide valuable insight into the cellular activities and biological processes in neurons in the development of drug addiction.     

Glutamate and Brain Glutaminases in Drug Addiction

Glutamate is the principal excitatory neurotransmitter in the central nervous system and its actions are related to the behavioral effects of psychostimulant drugs. In the last two decades, basic neuroscience research and preclinical studies with animal models are suggesting a critical role for glutamate transmission in drug reward, reinforcement, and relapse. Although most of the interest has been centered in post-synaptic glutamate receptors, the presynaptic synthesis of glutamate through brain glutaminases may also contribute to imbalances in glutamate homeostasis, a key feature of the glutamatergic hypothesis of addiction. Glutaminases are the main glutamate-producing enzymes in brain and dysregulation of their function have been associated with neurodegenerative diseases and neurological disorders; however, the possible implication of these enzymes in drug addiction remains largely unknown. This mini-review focuses on brain glutaminase isozymes and their alterations by in vivo exposure to drugs of abuse, which are discussed in the context of the glutamate homeostasis theory of addiction. Recent findings from mouse models have shown that drugs induce changes in the expression profiles of key glutamatergic transmission genes, although the molecular mechanisms that regulate drug-induced neuronal sensitization and behavioral plasticity are not clear.     

Experimental genetic approaches to addiction

Drugs of abuse are able to elicit compulsive drug-seeking behaviors upon repeated administration, which ultimately leads to the phenomenon of addiction. Evidence indicates that the susceptibility to develop addiction is influenced by sources of reinforcement, variable neuroadaptive mechanisms, and neurochemical changes that together lead to altered homeostasis of the brain reward system. Addiction is hypothesized to be a cycle of progressive dysregulation of the brain reward system that results in the compulsive use and loss of control over drug taking and the initiation of behaviors associated with drug seeking. The view that addiction represents a pathological state of reward provides an approach to identifying the factors that contribute to vulnerability, addiction, and relapse in genetic animal models.     

Gene expression profiling of the rewarding effect caused by methamphetamine in the mesolimbic dopamine system

Methamphetamine, a commonly used addictive drug, is a powerful addictive stimulant that dramatically affects the CNS. Repeated METH administration leads to a rewarding effect in a state of addiction that includes sensitization, dependence, and other phenomena. It is well known that susceptibility to the development of addiction is influenced by sources of reinforcement, variable neuroadaptive mechanisms, and neurochemical changes that together lead to altered homeostasis of the brain reward system. These behavioral abnormalities reflect neuroadaptive changes in signal transduction function and cellular gene expression produced by repeated drug exposure. To provide a better understanding of addiction and the mechanism of the rewarding effect, it is important to identify related genes. In the present study, we performed gene expression profiling using microarray analysis in a reward effect animal model. We also investigated gene expression in four important regions of the brain, the nucleus accumbens, striatum, hippocampus, and cingulated cortex, and analyzed the data by two clustering methods. Genes related to signaling pathways including G-protein-coupled receptor-related pathways predominated among the identified genes. The genes identified in our study may contribute to the development of a gene modeling network for methamphetamine addiction.