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; 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.

发展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。这样的特征涉及对激励显着性属性的承诺 与药物相关的提示，使此类提示具有“吸引人”和“磁性”，并能够煽动药物 寻求行为。签名跟踪大鼠（STS）接近并接触帕夫洛维亚条件刺激以获取食物 他们的对应者，目标追踪者（GTS）也了解此类提示的预测性质，但他们没有 接近他们。 STS已被广泛证明，很容易发生类似成瘾的人 因此，行为已被确立为成瘾脆弱性的主要动物模型。因为 注意力异常的障碍被认为是心理特征的重要组成部分 与成瘾脆弱性相关，我们证明了STS暴露了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的特征与相对较低的胆碱能神经调节水平相对较低的假设一致 将受试者偏离目标定向的关注，而不是提示驱动（或自下而上）的注意力。我们也是 表明，与GTS相比，帕夫洛维亚可卡因提示的存在未能增加胆碱能的水平 STS中的神经调节，从而通过提示和提示指导的行为促进了注意力。提议 研究将首先检验以下假设：神经元胆碱转运蛋白（CHT）动员的失败 对胆碱能神经元的刺激的反应是一种细胞机制，该机制占了衰减的能力 用于STS中的胆碱能神经调节。其次，我们将通过实验衰减来检验以下假设 CHT功能和抑制基本前脑胆碱能活性，标志跟踪行为表现出来，在GTS中， 注意力控制减少了，GTS更有可能接近经典的可卡因提示。 第三，基于表明刺激α4β2*烟碱乙酰胆碱受体（NACHRS）的证据 介导胆碱能神经调节对皮质回路的影响，我们将测试以下假设：在STS中，这种假设 治疗促进目标跟踪，改善注意力控制并降低可卡因提示的程度 控制行为。这项研究将共同​​证明胆碱能 - 注意定义是必不可少的 成瘾脆弱性特征的组成部分，即失调的CHT是索引的神经标志物 签名跟踪以及可以通过上调胆碱能来逆转签名和相关的漏洞 皮质的神经调节。