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: 9567913
• 负责人: SIMON Barak CAINE
• 金额: $ 8.66万
• 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/9567913
• 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 Mellitus; 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 group; 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.

总结 据估计，酒精使用障碍影响着1700万美国人，给个人和家庭带来了巨大的损失。 社会虽然现有的治疗和咨询可以有效地在一些饮酒者， 仍然难以实现。胰高血糖素样肽1（GLP-1）是一种既具有激素， 神经递质功能它在消化道中产生，调节血糖和食物摄入， GLP-1受体激动剂在临床上用于控制2型糖尿病。GLP-1也是在 GLP-1受体在成瘾的重要脑区表达，如腹侧 被盖区和延髓核。新出现的证据表明，一种或多种GLP-1受体 变体与酒精使用障碍相关，并调节乙醇在人体中的作用，GLP-1 1受体激动剂可以减少啮齿类动物的乙醇摄入量。这项研究的长期目标是， 从实验室动物的分子和行为研究到临床试验， 并优化GLP-1受体激动剂作为酒精使用障碍的治疗方法。目标是 目前的研究是了解GLP-1受体激动剂如何调节酒精使用，在电路/机制 水平目的1是鉴定GLP-1受体群体，这些群体是介导GLP-1降低所必需的和足够的。 乙醇摄入，使用GLP-1受体激动剂Exendin-4或GLP-1受体的微量输注 拮抗剂Exendin（9-39）进入腹侧被盖区，延髓核，脑室旁区， 下丘脑或小鼠杏仁核的中央区域。全身施用Exendin-4，和 非脑渗透剂Exendin-4融合分子进行比较。GLP-1受体配体 调节食物和液体的摄入量，使得很难将对乙醇的影响从 对消费行为的影响。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 比色法目的2是确定Exendin-4处理对乙醇诱导的神经元活动的影响， 急性和持续性变化引起的乙醇摄入量。本研究将采用免疫组化检测 立即早期基因c-Fos作为神经元活动的标志，在小鼠脑切片中允许自我- 静脉注射乙醇至少三周，或每天饮用乙醇至少四周。 对照组将分别自我给予生理盐水和仅饮水。在纹状体组织中，c-Fos 还将在细胞水平上评价表达，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， 将测定所有实验组的血液乙醇水平。