Glucagon-like peptide-1 modulation of alcohol effects

摘要 据估计，酒精使用障碍影响了1700万美国人，给个人和 社会。尽管可用的治疗和咨询对一些饮酒者有效，但长期的康复 仍然很难实现。胰升糖素样肽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也是在 大脑，GLP-1受体在大脑中对成瘾很重要的区域表达，如腹侧 被盖区和伏隔核。新的证据表明，一个或多个GLP-1受体 突变与人类的酒精使用障碍和乙醇的调节作用有关，而且GLP- 1受体激动剂可减少啮齿类动物的乙醇摄入量。这项研究的长期目标是，在 从实验室动物的分子和行为研究到临床试验的合作，是为了验证 并优化GLP-1受体激动剂作为酒精使用障碍的治疗方法。我们的目标是 目前的研究是为了了解GLP-1受体激动剂如何在电路/机制上调节酒精使用 水平。目标1是确定GLP-1受体种群，这是必要的和充分的，以调节 微量输注GLP-1受体激动剂Exendin-4或GLP-1受体的乙醇摄入 拮抗剂Exendin(9-39)进入腹侧被盖区、伏隔核、室旁区 小鼠的下丘脑，或杏仁核的中央区域。全身性给药Exendin-4和 非脑穿透性Exendin-4融合分子，将进行评价以作比较。GLP-1受体配体 调节食物和液体的摄入量，使人们很难区分酒精摄取的影响 对消费行为的总体影响。因此，目前的研究将利用静脉注射 酒精自我给药作为酒精强化和饮酒复发的非口服试验 化验。目的2确定Exendin-4处理对乙醇诱导的神经元活动的影响，两者 酒精摄入引起的急性和持续性变化。这一目标将使用免疫组织化学检测 即刻早期基因c-Fos作为神经元活动的标志，在允许自体发育的小鼠的脑片中 静脉注射乙醇至少三周，或每天喝乙醇至少四周。 对照组将分别自我注射生理盐水和只喝水。在纹状体组织中，c-Fos 表达也将在细胞水平上进行评估，区分直接和间接途径 利用在特定神经元类型中表达荧光报告的转基因小鼠培养刺状神经元。 所有试验组的血液酒精水平都将被测定。

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.