Glucagon-like peptide-1 modulation of alcohol effects

总结 在全球范围内，有害使用酒精在2016年造成300多万人死亡。这是一个更大的影响， 死亡率高于糖尿病、高血压、消化系统疾病或道路伤害。仅在美国， 据估计，AUD影响了1700万人，给个人和社会带来了巨大的代价。 尽管现有的治疗和咨询对一些饮酒者有效，但AUD是一种严重的 治疗不足和长期康复仍然难以实现。胰高血糖素样肽-1 是一种具有激素和神经递质功能的肽。它产生于消化道， 调节血糖和食物摄入，GLP-1受体激动剂在临床上用于管理2型糖尿病 糖尿病和肥胖症。GLP-1也在脑中产生，GLP-1受体在脑中表达。 对成瘾有重要影响的区域。有证据表明，一种或多种GLP-1受体变体与 GLP-1受体激动剂可以减少乙醇对人体的影响， 实验室动物的摄入量。这项研究的长期目标，在一个跨越分子和 从实验动物行为研究到临床试验，是为了验证和优化GLP-1受体激动剂 作为AUD的治疗方法。本申请是为了支持在此范围内的明确定义的项目。 正在进行的调查 本研究的目的是了解GLP-1受体激动剂如何调节酒精使用， 电路级和行为级。在目的1中，GABA能神经元和多巴胺能神经元的作用， GLP-1受体激动剂介导的自愿饮酒减少中的海马和侧隔 将评估摄入量。目的1a将联合收割机结合表达GLP-1的基因工程雄性和雌性小鼠， 全身和颅内微量输注选择性GLP-1后特定神经元类型中的GLP-1受体 受体激动剂毒蜥外泌肽-4，以检验GLP-1受体在多巴胺能或 GABA能神经元分别足以减少酒精摄入。aim 1b将使用基因 高时间分辨率的编码多巴胺指示剂来检验exendin-4 海马或侧隔微量输注抑制酒精诱导的细胞外 多巴胺在脑桥核在目标2中，每日GLP-1对酒精戒断症状的影响 受体激动剂治疗（在酒精接触期间或在强迫禁欲期间给予，两个实验）将 被评价。含酒精的流质饮食将用于诱导男性和女性的酒精依赖 小鼠，并且将使用急性体细胞毒性终点评估戒断症状的严重程度。 症状，以及使用焦虑样行为，快感缺乏， 昼夜活动模式和自愿饮酒量的变化，超过四周的禁欲。血液 在所有实验组中测定乙醇水平。

SUMMARY Globally, harmful use of alcohol killed more than 3 million people in 2016. This is a greater effect on mortality than diabetes, hypertension, digestive diseases, or road injuries. In the USA alone, alcohol use disorder (AUD) is estimated to affect 17 million people, with great costs to the individual and to society. Although available therapies and counseling can be effective in some drinkers, AUD is a severely undertreated condition and 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 and obesity. GLP-1 is also produced in the brain, and GLP-1 receptors are expressed in brain regions important in addictions. Evidence suggests that one or more GLP-1 receptor variants are associated with AUD and modulate effects of ethanol in humans, and that GLP-1 receptor agonists can reduce ethanol intake in laboratory animals. 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 AUD. The present application is to support a well-defined project within this ongoing line of investigation. The goal for the present studies is to understand how GLP-1 receptor agonists modulate alcohol use at a circuit level and at a behavioral level. In Aim 1, the roles of GABAergic and glutamatergic neurons in hippocampus and in lateral septum in GLP-1 receptor agonist-mediated decreases in voluntary alcohol intake will be evaluated. Aim 1a will combine genetically engineered male and female mice expressing GLP- 1 receptors in specific neuron types with systemic and intracranial microinfusions of the selective GLP-1 receptor agonist exendin-4 to test the hypothesis that stimulation of GLP-1 receptors in glutamatergic or GABAergic neurons, respectively, is sufficient to reduce alcohol intake. Aim1b will use a genetically encoded dopamine indicator with high temporal resolution to test the hypothesis that exendin-4 microinfusion into the hippocampus or lateral septum suppresses alcohol-induced increases in extracellular dopamine in the nucleus accumbens. In Aim 2, the effects on alcohol withdrawal symptoms of daily GLP-1 receptor agonist treatment (given during alcohol access or during forced abstinence, two experiments) will be evaluated. Alcohol-containing liquid diet will be used to induce alcohol dependence in male and female mice, and the severity of withdrawal symptoms will be assessed using endpoints of acute somatic symptoms, as well as more prolonged affective symptoms using tests of anxiety-like behavior, anhedonia, diurnal activity patterns, and change in voluntary alcohol consumption, over four weeks of abstinence. Blood ethanol levels will be determined in all experimental groups.