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: 10440417
• 负责人: MARTIN F SARTER
• 金额: $ 38.36万
• 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/10440417
• 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; addiction liability; 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.

导致成瘾的危险因素包括皮层和皮层下区域的结构异常