Alcohol Action in the Brain Reward Circuit

大脑奖赏回路中的酒精作用

• 批准号: 9063492
• 负责人: HITOSHI MORIKAWA
• 金额: $ 24.5万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9063492
• 关键词: Adolescent; Affect; Alcohol consumption; Alcoholism; Alcohols; Animals; Area; Autoreceptors; Behavior Control; Behavioral Assay; Binge Eating; Brain; Carbohydrates; Clinical; Consumption; DRD2 gene; Data; Development; Diet; Dopamine; Dopamine D2 Receptor; Electrophysiology (science); Ethanol; Fatty acid glycerol esters; Food; Funding; Future; Glutamates; Health; Housing; Individual; Inositol; Intake; Lead; Learning; Life; Life Experience; Long-Term Potentiation; Measures; Mediating; Memory; Metabotropic Glutamate Receptors; Methodology; Microinjections; Midbrain structure; Molecular; Monitor; N-Methyl-D-Aspartate Receptors; Neurobiology; Output; Pathway interactions; Pharmacotherapy; Prevention strategy; Process; Protocols documentation; Rattus; Rewards; Risk; Signal Transduction; Signaling Molecule; Slice; Social isolation; Staging; Stimulus; Synapses; Synaptic plasticity; System; Testing; Time; Ventral Tegmental Area; Withdrawal; Work; addiction; alcohol exposure; alcohol response; alcohol sensitivity; conditioning; desensitization; dopamine system; dopaminergic neuron; drug of abuse; early adolescence; experience; feeding; fluorescence imaging; mesolimbic system; neuroadaptation; neurobiological mechanism; paired stimuli; patch clamp; postnatal; pre-clinical; preference; research study; social; transmission process; treatment strategy

DESCRIPTION (provided by applicant): The mesolimbic dopaminergic system originating in the midbrain ventral tegmental area (VTA) is critically involved in the development of alcoholism. During the previous round of funding of this project, two types of neuroadaptive changes were identified in VTA dopamine neurons after repeated alcohol (ethanol) exposure: 1) enhanced synaptic plasticity of NMDA receptor-mediated glutamatergic transmission and 2) increased dopamine-induced autoinhibition of dopamine neuron activity mediated by somatodendritic D2 autoreceptors. These changes will promote the development of alcoholism by 1) facilitating the formation of powerful and enduring memories of ethanol-associated stimuli and 2) causing reduced dopaminergic output during withdrawal, which drives compulsive ethanol intake to compensate for dopamine deficits via ethanol stimulation of dopamine neuron activity. Clinical and preclinical evidence indicates that negative life experiences, such as prolonged social isolation or compulsive eating of calorie-dense palatable food, especially during early stages of life, increase an individual's risk of developing alcoholism both concurrently and in the future. However, the neurobiological mechanisms underlying the effects of these experiences are not well understood. The current proposal will investigate how VTA dopamine neurons are affected by prolonged social isolation (Aims 1 and 2) and extended access to high fat/carbohydrate palatable food ('cafeteria diet') (Aims 3 and 4) during early adolescence in rats. The overriding hypothesis is that these experiences will increase alcoholism vulnerability by enhancing NMDA receptor plasticity and dopamine-induced autoinhibition in the VTA. Brain slice experiments (Aims 1 and 3) will employ patch-clamp electrophysiology, confocal fluorescence imaging, and photolytic application of signaling molecules to determine the cellular and molecular mechanisms involved. These ex vivo methodologies will be combined with behavioral assays (Aims 2 and 4) to elucidate the neurobiological mechanisms underlying the vulnerability to develop alcoholism.

描述（由申请人提供）：起源于中脑腹侧被盖区（VTA）的中脑边缘多巴胺能系统与酒精中毒的发生密切相关。在该项目的上一轮资助期间，在重复酒精（乙醇）暴露后，在VTA多巴胺神经元中确定了两种类型的神经适应性变化：1）NMDA受体介导的突触可塑性增强，以及2）增加多巴胺诱导的多巴胺神经元活动的自抑制，由体树突D2自受体介导。这些变化将通过以下方式促进酒精中毒的发展：1）促进乙醇相关刺激的强大和持久记忆的形成; 2）在戒断过程中导致多巴胺能输出减少，这促使强迫性乙醇摄入，以通过乙醇刺激多巴胺神经元活动来补偿多巴胺缺乏。临床和临床前证据表明，负面的生活经历，如长期的社会孤立或强迫性食用热量密集的美味食物，特别是在生命的早期阶段，增加了个体同时和未来发展酒精中毒的风险。然而，这些经验的影响背后的神经生物学机制还没有得到很好的理解。目前的建议将研究如何VTA多巴胺神经元受到长期的社会隔离（目标1和2）和延长获得高脂肪/碳水化合物可口的食物（“自助餐”）（目标3和4）在青春期早期大鼠。最重要的假设是，这些经验将增加酒精中毒的脆弱性，通过增强NMDA受体的可塑性和多巴胺诱导的自抑制腹侧被盖区。脑切片实验（目标1和3）将采用膜片钳电生理学、共聚焦荧光成像和信号分子的光解应用，以确定所涉及的细胞和分子机制。这些离体方法学将与行为测定（目标2和4）相结合，以阐明易患酒精中毒的神经生物学机制。