Alcohol Action in the Brain Reward Circuit

描述(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。在本项目的前一轮资助中，在反复酒精暴露后，VTA多巴胺神经元发现了两种类型的神经适应性变化：1)NMDA受体介导的谷氨酸能传递的突触可塑性增强；2)多巴胺诱导的由躯体树突D2自体受体介导的多巴胺神经元活动的自身抑制。这些变化将通过以下方式促进酒精中毒的发展：1)促进对酒精相关刺激的强大而持久的记忆的形成；2)在戒断过程中导致多巴胺能输出减少，从而通过乙醇刺激多巴胺神经元活动来驱使强迫的乙醇摄入来弥补多巴胺的缺乏。临床和临床前证据表明，消极的生活经历，如长期的社会隔离或强迫食用高卡路里的可口食物，特别是在生命的早期阶段，会增加个人同时和未来发展成酒精中毒的风险。然而，这些经历的影响背后的神经生物学机制还没有被很好地理解。目前的提案将研究VTA多巴胺神经元如何在青春期早期受到长期的社会隔离(目标1和2)和更多地获得高脂肪/碳水化合物可口食物(自助餐饮食)(目标3和4)的影响。最重要的假设是，这些经历将通过增强NMDA受体的可塑性和多巴胺诱导的VTA中的自我抑制来增加酒精中毒的易感性。脑片实验(目标1和3)将使用膜片钳电生理学、共聚焦荧光成像和信号分子的光解应用来确定所涉及的细胞和分子机制。这些体外方法将与行为分析(目标2和4)相结合，以阐明酒精中毒易感性背后的神经生物学机制。

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.