Alcohol Action in the Brain Reward Circuit

描述（由申请人提供）：起源于中脑腹侧被盖区（VTA）的中边缘多巴胺能系统在酒精中毒的发展中起关键作用。在本项目的上一轮资助中，反复接触酒精（乙醇）后，在VTA多巴胺神经元中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)多巴胺诱导的体树突D2自受体介导的多巴胺神经元活性的自抑制增强。这些变化将促进酒精中毒的发展：1)促进酒精相关刺激的强大和持久记忆的形成；2)导致戒断期间多巴胺能输出减少，从而导致强迫性乙醇摄入，通过乙醇刺激多巴胺神经元活动来补偿多巴胺的缺陷。临床和临床前证据表明，负面的生活经历，如长期的社会隔离或强迫进食高热量的美味食物，特别是在生命的早期阶段，增加了个人同时和未来发展为酗酒的风险。然而，这些经历的影响背后的神经生物学机制还没有得到很好的理解。目前的提案将研究大鼠青春期早期长时间的社会隔离（目标1和2）和长时间获得高脂肪/碳水化合物美味食物（“自助餐厅饮食”）（目标3和4）如何影响VTA多巴胺神经元。最重要的假设是，这些经历会通过增强NMDA受体的可塑性和多巴胺诱导的VTA自抑制来增加酒精中毒的易感性。脑切片实验（目标1和目标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来确定所涉及的细胞和分子机制。这些离体方法将与行为分析相结合（目的2和4），以阐明易患酒精中毒的神经生物学机制。

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.