Orbitofrontal coding of alcohol preference and compulsive drinking

酒精偏好和强迫性饮酒的眶额编码

• 批准号: 9315670
• 负责人: DAVID E MOORMAN
• 金额: $ 18.94万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9315670
• 关键词: Address; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Animal Model; Animals; Area; Automobile Driving; Behavior; Behavioral; Catheters; Chronic; Code; Consumption; Cues; Desire for food; Development; Disease; Electrophysiology (science); Employee Strikes; Ethanol; Exhibits; Female; Functional disorder; Goals; Health; Heavy Drinking; Home environment; Implant; In Vitro; Individual; Individual Differences; Measures; Motivation; Neurons; Outcome; Pathologic; Pattern; Performance; Pharmacology; Plant Roots; Population; Predisposition; Punishment; Quinine; Rattus; Research; Resistance; Rewards; Role; Self Administration; Sex Characteristics; Signal Transduction; Stimulus; Sucrose; System; Testing; Work; addiction; alcohol abuse therapy; alcohol behavior; alcohol craving; alcohol cue; alcohol effect; alcohol exposure; alcohol response; alcohol reward; alcohol seeking behavior; alcohol testing; alcohol use disorder; base; conditioning; craving; drinking; drug of abuse; expectation; experience; experimental study; in vivo; male; neuromechanism; preference; relating to nervous system; response

PROJECT SUMMARY/ABSTRACT The orbitofrontal cortex (OFC) has been heavily implicated in reward valuation and seeking, and there is a strong association between OFC dysfunction and addiction to drugs of abuse. Accumulating evidence suggests that OFC may be a critical node in the development of compulsive alcohol seeking in alcohol use disorders. Despite the clear relevance of OFC function to alcohol use, however, there have been few direct studies of this relationship and no studies of OFC neuron function during alcohol seeking. We will investigate OFC function during ethanol expectation, seeking, taking, and consumption, as well as how OFC is disrupted in compulsive ethanol motivation following chronic use. Based on previous results, we expect OFC activity to underlie ethanol preference and motivation and to be upregulated during enhanced motivation in compulsive ethanol use. We will record the activity of OFC neuron ensembles in different groups of rats given either short (~1 month) or long (~4 months) access to ethanol. Both male and female rats will be studied in order to understand how differential OFC function underlies previously described sex differences in ethanol use. In short-access animals, we and others have observed striking individual differences in preference for ethanol. We hypothesize that OFC activity will positively correlate with ethanol motivation and negatively correlate with consumption in this group. In long-access animals, ethanol drinking becomes compulsive – characterized by increased motivation and resistance to adulteration with quinine, which is normally aversive. We hypothesize that, in punishment-resistant compulsive ethanol seekers, OFC neurons will exhibit pathologically enhanced activation during ethanol cues and seeking and diminished inhibition during consumption. In both studies, we will also manipulate OFC activity to assess a causal relationship between OFC and ethanol use. We hypothesize that OFC inhibition will decrease preference and motivation for ethanol. These studies will provide new information regarding the specific ethanol-related behaviors driven by OFC activation as well as mechanisms underlying susceptibility for excessive drinking and problematic alcohol use. By drawing direct connections between OFC function and the transition to compulsive alcohol seeking, these studies have a strong potential to identify an important new target for treatment of alcohol use disorders. The two Specific Aims to be investigated in this project are: 1. Identify OFC signals related to individual differences in behavioral components of ethanol use using Pavlovian and operant tests of ethanol expectation and seeking in short-access rats. We will probe the relationship between OFC function and ethanol motivation focusing on individual and sex differences in behavior. 2. Identify OFC signals related to compulsive motivation for alcohol using the same tests in long-access rats who demonstrate elevated, punishment-resistant ethanol seeking. We will probe how OFC activity related to ethanol seeking and consumption is enhanced or suppressed after chronic ethanol use.

项目总结/摘要 眶额皮层（OFC）与奖励评估和寻求有很大关系， 眶额皮层功能障碍与药物滥用成瘾之间存在密切联系。越来越多的证据表明 OFC可能是酒精使用障碍中强迫性酒精寻求发展的关键节点。 尽管眶额皮层功能与饮酒有明显的相关性，但是，很少有直接的研究 在酒精寻求过程中OFC神经元功能的研究。我们将研究OFC函数 在乙醇期望，寻求，服用和消费期间，以及OFC如何在强迫性 长期使用乙醇的动机。根据以前的结果，我们预计OFC活动是乙醇的基础 偏好和动机，并在强迫性乙醇使用的动机增强期间上调。 我们将记录不同组大鼠的眶额皮层神经元群的活动， 月）或长期（约4个月）获得乙醇。为了了解雄性和雌性大鼠， OFC功能的差异如何成为先前描述的乙醇使用性别差异的基础。在短期访问 在动物中，我们和其他人已经观察到对乙醇的偏好存在显著的个体差异。我们假设 OFC活动将与乙醇动机呈正相关，与消费呈负相关， 这个团体。在长期接触的动物中，乙醇饮用变得强迫性-其特征是增加 动机和抵制掺入奎宁，这通常是令人厌恶的。我们假设，在 对于惩罚抵抗的强迫性乙醇寻求者，OFC神经元将表现出病理性增强的激活 在乙醇线索和寻求和消费过程中减少抑制。在这两项研究中，我们还将 操纵OFC活动，以评估OFC和乙醇使用之间的因果关系。我们假设 OFC抑制将降低对乙醇的偏好和动机。 这些研究将提供有关特定乙醇相关行为的新信息， 眶额皮层激活以及过度饮酒和问题酒精易感性的潜在机制 使用.通过将眶额皮层功能与强迫性酒精寻求之间的直接联系， 这些研究有很大的潜力来确定治疗酒精使用障碍的重要新靶点。 该项目将研究的两个具体目标是： 1.识别与乙醇使用行为成分个体差异相关的OFC信号， 巴甫洛夫和操作测试乙醇的期望和寻求短期访问大鼠。我们将探索 OFC功能和乙醇动机的关系，侧重于行为的个体和性别差异。 2.在长距离接触中使用相同的测试识别与酒精强迫动机相关的OFC信号 那些表现出较高的、对惩罚有抵抗力的乙醇寻求的大鼠。我们将探讨OFC活动如何与 在慢性乙醇使用后，乙醇寻求和消费增加或抑制。