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

基本信息

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
项目类别：
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

项目摘要

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之一涉及将激励显着性归因于的倾向。与毒品相关的线索，使这些线索具有“吸引力”和“磁性”，并且能够煽动毒品信号追踪大鼠（ST）在接近并接触巴甫洛夫条件刺激以获取食物时。他们的部门，目标追踪者（GT），也了解这些线索的预测性质，但他们不接近它们已被普遍证明很容易产生类似成瘾的症状。行为，因此已被确立为成瘾脆弱性的主要动物模型。注意力异常的损害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 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来介导的。 ST 的特征与胆碱能神经调节水平相对较低的假设是一致的我们还使受试者偏离目标导向的注意力，转向提示驱动（或自下而上）的注意力。结果表明，与 GT 相比，巴甫洛夫可卡因提示的存在不能增加胆碱能水平 ST 中的神经调节，通过提示促进注意力捕获，从而促进提示导向的行为。研究将首先检验以下假设：神经元胆碱转运蛋白（CHT）无法动员对胆碱能神经元刺激的反应是导致能力减弱的细胞机制其次，我们将通过实验减弱来检验这一假设。 CHT 功能并抑制基础前脑胆碱能活动，体征跟踪行为表现出来，并且在 GT 中，注意力控制减弱，GT 更有可能接近经典条件可卡因线索。第三，基于证据表明α4β2*烟碱乙酰胆碱受体（nAChRs）的刺激介导胆碱能神经调节对皮质回路的影响，我们将检验以下假设：在 ST 中，这样的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总之，这项研究将证明胆碱能注意力缺陷是至关重要的。成瘾脆弱性特征的组成部分，失调的 CHT 是该特征的神经标志物体征跟踪，并且可以通过上调胆碱能来逆转体征跟踪和相关的漏洞皮质的神经调节。