Optogenetic Analysis of Different Forms of Aversion-Resistant Ethanol Intake

不同形式的抗厌恶乙醇摄入的光遗传学分析

基本信息

批准号：
8725027
负责人：
Frederic Woodward Hopf
金额：
$ 18.2万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8725027
关键词：
Addictive Behavior Address Alcohol consumption Alcoholic Beverages Alcoholism Animal Model Area Aversive Stimulus Behavior Behavioral Brain region Clinical Cocaine Data Development Drug resistance Economics Electrophysiology (science)Employee Strikes Ethanol Figs - dietary Future Glutamate Receptor Glutamates Goals Halorhodopsins Human In Vitro Insula of Reil Intake Intervention Knowledge Lasers Light Mediating Medical Methods Modality Modeling Molecular Motor N-Methyl-D-Aspartate Receptors Neurons Nicotine Nucleus Accumbens Obsessive compulsive behavior Pharmacology Play Presynaptic Terminals Proteins Quinine Rattus Receptor Signaling Relapse Resistance Rodent Role Saccharin Saline Self Administration Sensory Taste Perception Techniques Testing addiction alcohol seeking behavior alcohol use disorder alcoholism therapy base human disease in vivo inhibitor/antagonist interest neural circuit new therapeutic target novel optogenetics problem drinker public health relevance relating to nervous system research study social somatosensory

项目摘要

DESCRIPTION (provided by applicant): Human alcoholics undergo major periods of relapse and compulsive alcohol seeking, where alcohol intake persists despite adverse economic, social, and physical consequences. Although compulsion represents a major clinical hurdle to treatment of alcoholism by promoting relapse and continued alcohol intake, virtually nothing is known about molecular and neuronal mechanisms that drive compulsive aspects of alcohol intake. Human studies suggest that compulsive behavior may be regulated by frontal cortical areas that send glutamatergic inputs to the nucleus accumbens core (NAcore), and NAcore glutamate receptor signaling is critical for the expression of many motivated, addictive, and perhaps habitual behaviors. The Insular cortex in particular is implicated in generating strong drives that promote addiction, at least for nicotine. Here, the major goal of this proposal is an exploratory set of rat experiments addressing whether a common molecular circuit (Insula inputs to the NAcore and activation of NAcore NMDA receptors) drives different forms of aversion-resistant ethanol intake, which may model some aspects of human compulsive alcohol intake. We hypothesize, based in part on extensive preliminary data, that this common molecular circuit promotes aversion-resistant ethanol intake regardless of intake model (drinking ethanol from a bottle, operant lever pressing for ethanol) or the sensory modality of the aversive stimulus paired with ethanol (taste for quinine, somatosensory for footshock). Thus, Specific Aim 1 uses state-of-the- art optogenetic techniques in vivo to examine whether inhibiting Insula-to-NAcore inputs similarly reduces ethanol intake during the different forms of aversion-resistant ethanol intake. In particular, we use halorhodopsin, a light-activated inhibitory protein than can be viraly expressed within a particular brain region to selectively modulate axon terminals. Also, our in vitro electrophysiology experiments find enhanced NMDAR function under Insula-to-NAcore inputs, and thus Specific Aim 2 examines whether pharmacological block of NMDARs within the NAcore also inhibits aversion-resistant ethanol intake with different intake models and different aversive stimuli paired with ethanol. We also examine whether Insula-NAcore inputs and NAcore NMDARs mediate intake when ethanol is not overtly paired with an aversive stimuli. Glutamatergic inputs to the NAcore likely play a central role in the expression of aversion-resistant alcohol intake, and our use of optogenetics in combination with intracranial pharmacology is likely to provide critical and therapeutically relevant information about molecular mechanisms underlying compulsive alcohol intake.

描述（由申请人提供）：人类酒精中毒经历了重大复发和强迫性饮酒时期，尽管经济，社会和身体后果不利，但酒精摄入量仍然存在。尽管强迫是通过促进复发和持续的酒精摄入来治疗酒精中毒的主要临床障碍，但实际上，关于驱动酒精摄入强迫性方面的分子和神经元机制几乎一无所知。人类的研究表明，强迫行为可能受到额叶皮质区域的调节，这些皮质区域将谷氨酸能输入发送到伏伏核（Nacore）和Nacore谷氨酸受体信号传导对许多动机，成瘾性和可能的习惯性行为的表达至关重要。尤其是岛状皮质尤其涉及产生促进成瘾的强驱动器，至少对于尼古丁。在这里，该提案的主要目的是探索性的大鼠实验集，该实验涉及通用分子回路（Nacore NMDA受体的岛输入和激活NACORE NMDA受体）是否会驱动不同形式的抗厌食乙醇摄入量，这可能会模拟人类强迫性酒精摄入的某些方面。我们假设基于广泛的初步数据假设，这种常见的分子电路可促进抗厌恶性乙醇的摄入量，而不管摄入模型（从瓶中喝乙醇，供应乙醇的操作杠杆）或对乙醇的感觉厌恶刺激的感觉方式与乙醇搭配（对奎因氨酸的味道）。因此，特定的目标1在体内使用最新的光学遗传学技术来检查抑制岛 - 纳向 - 纳龙的输入是否在不同形式的抗厌食耐药性乙醇摄入量中类似地降低了乙醇的摄入量。特别是，我们使用甲莫淡宁，一种光激活的抑制蛋白比在特定大脑区域内表达的可以选择性调节轴突末端。同样，我们的体外电生理学实验在岛 - 纳龙输入下发现了NMDAR功能增强，因此具体的目标2检查了NACORE内NMDAR的药理学阻滞是否还可以抑制具有不同摄入量的抗厌恶性乙醇摄入剂，并具有不同的摄入量模型，并且与乙醇均与不同的厌食刺激。我们还检查了当乙醇与厌恶刺激配对时，Insula-Nacore输入和NACORE NMDAR是否会介导摄入。 Nacore的谷氨酸能输入可能在表达抗厌食症的酒精摄入量中起着核心作用，并且我们将光遗传学与颅内药理学结合使用，可能会提供有关强迫性酒精摄入剂的分子机制的关键和治疗相关信息。