Addiction liability, poor attentional control, and cholinergic deficiency

成瘾倾向、注意力控制能力差和胆碱能缺乏

• 批准号: 9925194
• 负责人: MARTIN F SARTER
• 金额: $ 38.64万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9925194
• 关键词: Accounting; Acetylcholine; Animal Model; Animals; Attention; Attentional deficit; Attenuated; Behavior; Behavior Control; Behavioral; Cell membrane; Characteristics; Choline; Cocaine; Cognitive; Conditioned Stimulus; Corpus striatum structure; Cues; Data; Development; Dissociation; Dopamine; Drug usage; Electric Stimulation; Excision; Exhibits; Failure; Food; Fostering; Freezing; Genotype; Goals; Impairment; Impulsivity; Learning; Magnetism; Mediating; Modification; Motivation; Nature; Neurons; Nicotinic Receptors; Performance; Persons; Pharmaceutical Preparations; Phenotype; Population; Process; Rattus; Relapse; Research; Resistance; Rewards; Risk Factors; Role; Structural defect; Structure; Substance Use Disorder; Synapses; Synaptosomes; System; Testing; Ubiquitination; Work; addiction; approach behavior; attentional control; basal forebrain; base; brain abnormalities; choline transporter; cholinergic; cholinergic neuron; designer receptors exclusively activated by designer drugs; directed attention; drug seeking behavior; improved; incentive salience; indexing; neurochemistry; neuroinflammation; neuroregulation; population based; psychologic; receptor; response; sustained attention; trait; treatment effect

Risk factors for developing addiction include structural abnormalities in cortical and subcortical regions and associated psychological traits. One such trait concerns the propensity for attribution of incentive salience to drug-associated cues, rendering such cues to be “attractive” and “magnetic” and capable of instigating drug- seeking behavior. Sign-tracking rats (STs) approach and contact a Pavlovian conditioned stimulus for food while their counterparts, the goal-trackers (GTs), also learn about predictive nature of such cues but they do not approach them. STs have been extensively demonstrated to be vulnerable for developing addiction-like behaviors and thus have been established as a major animal model of addiction vulnerability. Because impairments in attentional abnormalities are considered an essential component of psychological traits associated with addiction vulnerability, we demonstrated that STs exhibit relatively poor attentional performance that is mediated via low levels of cortical cholinergic neuromodulation. These behavioral and neurochemical characteristics of STs are consistent with the hypothesis that relatively low levels of cholinergic neuromodulation bias the subject away from goal-directed attention and toward cue-driven (or bottom-up) attention. We also showed that, in contrast to GTs, the presence of a Pavlovian cocaine cue fails to increase levels of cholinergic neuromodulation in STs, thereby fostering attention-capture by the cue and cue-directed behavior. The proposed research will first test the hypothesis that a failure of the neuronal choline transporter (CHT) to mobilize in response to stimulation of cholinergic neurons is a cellular mechanism accounting for the attenuated capacity for cholinergic neuromodulation in STs. Second, we will test the hypothesis that by experimentally attenuating CHT function and inhibiting basal forebrain cholinergic activity, sign-tracking behavior manifests and, in GTs, attentional control is diminished, and GTs are more likely to approach a classically conditioned cocaine cue. Third, based on evidence indicating that stimulation of α4β2* nicotinic acetylcholine receptors (nAChRs) mediates effects of cholinergic neuromodulation on cortical circuitry, we will test the hypothesis that, in STs, such a treatment fosters goal-tracking, improves attentional control and reduces the degree to which a cocaine cue controls behavior. Together, this research will demonstrate that cholinergic-attentional deficits are essential components of addiction vulnerability traits, that a dysregulated CHT is a neuromarker of the trait indexed by sign-tracking, and that sign-tracking and associated vulnerabilities can be reversed by upregulating cholinergic neuromodulation of the cortex.

形成成瘾的风险因素包括皮质和皮质下区域的结构异常， 相关的心理特征一个这样的特点涉及的倾向，归因于激励显着性， 药物相关的线索，使这些线索是“有吸引力的”和“磁性”，并能够煽动药物- 寻求行为。符号追踪大鼠（ST）接近并接触巴甫洛夫条件刺激以获取食物， 他们的对手，目标追踪者（GT），也了解这些线索的预测性质，但他们没有 接近他们。ST已被广泛证明是脆弱的发展成瘾样 行为，因此已被确立为成瘾脆弱性的主要动物模型。因为 注意力异常的损伤被认为是心理特征的重要组成部分 与成瘾易感性相关，我们证明ST表现出相对较差的注意力表现， 这是通过低水平的皮质胆碱能神经调节介导的。这些行为和神经化学 ST的特征与相对低水平的胆碱能神经调节 使受试者偏离目标导向的注意力，转向线索驱动（或自下而上）的注意力。我们也 表明，与GT相反，巴甫洛夫可卡因线索的存在不能增加胆碱能水平， 神经调节的ST，从而促进注意力捕获的线索和线索导向的行为。拟议 这项研究将首先检验神经胆碱转运蛋白（CHT）不能动员的假设， 对胆碱能神经元的刺激的反应是导致能力减弱的细胞机制 用于ST的胆碱能神经调节第二，我们将测试的假设，通过实验衰减 CHT功能和抑制基底前脑胆碱能活性，标志追踪行为表现出来，在GT中， 注意力控制减弱，GT更可能接近经典条件可卡因线索。 第三，基于证据表明刺激α4β2* 烟碱乙酰胆碱受体（nAChRs） 介导胆碱能神经调节对皮层回路的影响，我们将检验这一假设，在ST中， 治疗可以促进目标跟踪，改善注意力控制，降低可卡因暗示的程度。 控制行为。总之，这项研究将证明胆碱能注意力缺陷是必不可少的， 成瘾脆弱性特征的组成部分，CHT失调是一种神经标志物的特点索引 信号追踪，信号追踪和相关的脆弱性可以通过上调胆碱能神经来逆转， 大脑皮层的神经调节