Glucagon-like peptide-1 modulation of alcohol effects

胰高血糖素样肽-1 调节酒精效应

• 批准号: 9311531
• 负责人: SIMON Barak CAINE
• 金额: $ 10.63万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9311531
• 关键词: Abstinence; Acute; Affect; Agonist; Alcohol consumption; American; Amygdaloid structure; Animals; Behavioral; Biological Assay; Blood; Blood Glucose; Brain; Brain region; Chimeric Proteins; Chronic; Clinical; Clinical Trials; Cocaine; Collaborations; Consummatory Behavior; Consumption; Control Groups; Corpus striatum structure; Corticotropin-Releasing Hormone Receptors; Counseling; Data; Detection; Development; Diabetes prevention; Dopamine; Dopamine D2 Receptor; Dose; Eating; Ethanol; FOS gene; Food; Future; GLP-I receptor; Gastrointestinal tract structure; Genetically Engineered Mouse; Goals; Hormones; Human; Hypothalamic structure; Immediate-Early Genes; Individual; Intake; Intestines; Intravenous; Investigation; Laboratory Animals; Lead; Left; Ligands; Liquid substance; Measures; Mediating; Molecular; Mouse Strains; Mus; Nature; Neural Pathways; Neurons; Neurotransmitters; Non-Insulin-Dependent Diabetes Mellitus; Nucleus Accumbens; Oral; Palate; Pathway interactions; Peptides; Peripheral; Pharmaceutical Preparations; Population; Recovery; Relapse; Reporter; Research; Rodent; Saline; Self Administration; Self-Administered; Slice; Societies; Substance Use Disorder; System; Testing; Tissues; Transferrin; Transgenic Mice; Variant; Ventral Tegmental Area; Water; Work; addiction; alcohol effect; alcohol reinforcement; alcohol reward; alcohol seeking behavior; alcohol use disorder; behavioral study; cell type; cost; dopamine transporter; drinking; exenatide; experimental study; gamma-Aminobutyric Acid; glucagon-like peptide 1; nonhuman primate; obesity prevention; pre-clinical

SUMMARY Alcohol use disorder is estimated to affect 17 million Americans, with great costs to the individual and to society. Although available therapies and counseling can be effective in some drinkers, long-term recovery remains difficult to achieve. Glucagon-like peptide 1 (GLP-1) is a peptide that has both hormone and neurotransmitter functions. It is produced in the digestive tract and regulates blood sugar and food intake, and GLP-1 receptor agonists are used clinically to manage type 2 diabetes. GLP-1 is also produced in the brain, and GLP-1 receptors are expressed in brain regions important in addictions, such as the ventral tegmental area and the nucleus accumbens. Emerging evidence suggests that one or more GLP-1 receptor variants are associated with alcohol use disorder and modulate effects of ethanol in humans, and that GLP- 1 receptor agonists can reduce ethanol intake in rodents. The long-term goal of this research, in a collaboration spanning molecular and behavioral studies in laboratory animals to a clinical trial, is to validate and optimize GLP-1 receptor agonists as a treatment approach for alcohol use disorders. The goal for the present studies is to understand how GLP-1 receptor agonists modulate alcohol use, at a circuit/mechanism level. Aim 1 is to identify the GLP-1 receptor populations necessary and sufficient to mediate decreases in ethanol intake, using microinfusions of the GLP-1 receptor agonist Exendin-4 or the GLP-1 receptor antagonist Exendin(9-39) into the ventral tegmental area, nucleus accumbens, paraventricular region of the hypothalamus, or central region of the amygdala in mice. Systemic administration of Exendin-4, and of a non-brain penetrant Exendin-4 fusion molecule, will be evaluated for comparison. GLP-1 receptor ligands modulate food and fluid intake, making it difficult to separate effects on ethanol seeking specifically from effects on consummatory behaviors generally. Therefore, the present studies will make use of intravenous ethanol self-administration as a non-oral assay of ethanol reinforcement, as well as of a drinking relapse assay. Aim 2 is to determine the effects of Exendin-4 treatment on ethanol-induced neuronal activity, both acute and persistent changes induced by ethanol intake. This aim will use immunohistochemical detection of the immediate early gene c-Fos as a marker of neuronal activity, in brain slices from mice allowed to self- administer ethanol intravenously for at least three weeks, or to drink ethanol daily for at least four weeks. Control groups will self-administer saline and drink only water, respectively. In striatal tissues, c-Fos expression will also be evaluated at the cellular level, distinguishing between direct and indirect pathway medium spiny neurons by use of transgenic mice expressing a fluorescent reporter in specific neuron types. Blood ethanol levels will be determined in all experimental groups.

概括 据估计，酒精使用障碍影响了 1700 万美国人，给个人和家庭造成了巨大损失。 社会。尽管现有的治疗和咨询对某些饮酒者可能有效，但长期康复 仍难以实现。胰高血糖素样肽 1 (GLP-1) 是一种同时具有激素和 神经递质功能。它在消化道中产生，调节血糖和食物摄入量， GLP-1受体激动剂在临床上用于治疗2型糖尿病。 GLP-1 也生产于 GLP-1 受体在对成瘾起重要作用的大脑区域表达，例如腹侧 被盖区和伏隔核。新出现的证据表明，一种或多种 GLP-1 受体 变异体与酒精使用障碍相关并调节乙醇对人类的影响，并且 GLP- 1受体激动剂可以减少啮齿动物的乙醇摄入量。本研究的长期目标是 从实验动物的分子和行为研究到临床试验的合作，旨在验证 并优化 GLP-1 受体激动剂作为酒精使用障碍的治疗方法。目标为 目前的研究旨在了解 GLP-1 受体激动剂如何通过回路/机制调节酒精使用 等级。目标 1 是确定必要且足以介导 GLP-1 受体数量减少的 GLP-1 受体群。 乙醇摄入，使用 GLP-1 受体激动剂 Exendin-4 或 GLP-1 受体微量输注 拮抗剂 Exendin(9-39) 进入腹侧被盖区、伏隔核、室旁区 下丘脑，或小鼠杏仁核的中央区域。 Exendin-4 和 a 的全身给药 非脑渗透Exendin-4融合分子，将进行评估以进行比较。 GLP-1受体配体 调节食物和液体摄入量，因此很难区分对乙醇的影响 总体上对完成行为的影响。因此，目前的研究将利用静脉注射 乙醇自我给药作为乙醇强化以及饮酒复发的非口服测定 化验。目标 2 是确定 Exendin-4 治疗对乙醇诱导的神经元活动的影响， 乙醇摄入引起的急性和持续的变化。该目的将使用免疫组织化学检测 立即早期基因 c-Fos 作为神经元活动的标记，在小鼠的脑切片中进行自我观察 静脉注射乙醇至少三周，或每天饮用乙醇至少四个星期。 对照组将分别自行注射生理盐水并仅喝水。在纹状体组织中，c-Fos 表达也将在细胞水平上进行评估，区分直接途径和间接途径 通过使用在特定神经元类型中表达荧光报告基因的转基因小鼠来获得中等棘神经元。 将测定所有实验组的血液乙醇水平。