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: 9593624
• 负责人: MARTIN F SARTER
• 金额: $ 40.11万
• 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/9593624
• 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; 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.

成瘾的危险因素包括皮质和皮质下区域的结构异常以及 相关的心理特征。其中一个特征与激励显著的归因倾向有关 与毒品有关的线索，使这些线索具有吸引力和吸引力，并能够煽动毒品- 寻求行为。手势跟踪大鼠(STS)接近并接触巴甫洛夫条件刺激食物，同时 他们的同行，目标追踪者(GT)，也知道这种线索的预测性，但他们不知道 走近他们。STS已被广泛证明很容易发展成瘾样 并因此被确立为成瘾易感性的主要动物模型。因为 注意力异常的障碍被认为是心理特征的一个重要组成部分 与成瘾易感性有关，我们证明STS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来调节的。这些行为和神经化学物质 STS的特征与胆碱能神经调节水平相对较低的假设一致 让受试者远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 结果表明，与GTS相反，巴甫洛夫可卡因线索的存在不能增加胆碱能水平 STS中的神经调节，从而通过线索和线索引导行为培养注意力捕获。建议数 研究将首先检验这一假设，即神经元胆碱转运体(CHT)未能在 对胆碱能神经元刺激的反应是导致能力减弱的一种细胞机制 用于STS的胆碱能神经调节。其次，我们将检验这样的假设，即通过实验衰减 CHT功能和抑制基底前脑胆碱能活动，体征跟踪行为表现，在GTS， 注意力控制减弱，GT更有可能接近经典的条件可卡因提示。 第三，有证据表明，刺激α4β2*烟碱型乙酰胆碱受体(NAChRs) 介导胆碱能神经调节对皮质回路的影响，我们将检验这样的假设：在STS中， 治疗可以促进目标跟踪，改善注意力控制，并降低可卡因提示的程度 控制行为。总而言之，这项研究将证明胆碱能注意缺陷是必不可少的 成瘾易感性特征的组成部分，失调的CHT是该特征的神经标记物，通过 手势跟踪，手势跟踪和相关漏洞可以通过上调胆碱能来逆转 大脑皮层的神经调节。