GLP-1 Receptors and Psychostimulant Addiction

GLP-1 受体和精神兴奋剂成瘾

• 批准号: 8840923
• 负责人: AURELIO GALLI
• 金额: $ 19.11万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8840923
• 关键词: Agonist; Animals; Behavioral; Behavioral Assay; Biochemical; Biological Assay; Brain; Brain Chemistry; Brain region; Cellular Assay; Cerebral cortex; Clinical Research; Cocaine; Corpus striatum structure; Data; Diabetes Mellitus; Dopamine; Dopamine D2 Receptor; Dopamine Receptor; Dorsal; Drug Addiction; Drug Targeting; Drug abuse; Eating; FDA approved; Feeding behaviors; Genetic; Glucagon; Health; Heterogeneity; Hippocampus (Brain); Homeostasis; Human; Hypothalamic structure; Intervention; Knockout Mice; Knowledge; Laboratories; Lateral; Limbic System; Marketing; Mediating; Mediator of activation protein; Medical; Methods; Microinjections; Molecular; Mus; Neurobiology; Neurons; Neuropeptides; Non-Insulin-Dependent Diabetes Mellitus; Nucleus Accumbens; Outcome; Pattern; Peptides; Peripheral; Pharmaceutical Preparations; Phenotype; Play; Process; Property; Psychological reinforcement; Psychostimulant dependence; Public Health; Receptor Activation; Receptor Signaling; Rewards; Role; Signal Transduction; Site; Testing; Therapeutic; Therapeutic Effect; Translating; Ventral Tegmental Area; Viral; addiction; analog; base; behavioral pharmacology; brain circuitry; cholinergic neuron; cocaine exposure; conditioning; dopamine system; dopamine transporter; drug of abuse; drug reward; exenatide; food addiction; genetic approach; glucagon-like peptide; glucagon-like peptide 1; hedonic; improved; in vivo; incretin hormone; multidisciplinary; nerve supply; neurobiological mechanism; neurotransmission; novel; preference; presynaptic; psychostimulant; receptor; receptor expression; response; stimulant abuse; trafficking; uptake

DESCRIPTION (provided by applicant): Psychostimulant abuse and addiction is a crushing public health problem. Our laboratories have begun to decipher the functional effects of glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) stimulation on dopamine uptake, clearance, and trafficking of presynaptic dopamine transporters. GLP-1 is an incretin hormone and neuropeptide that is released in response to food intake. GLP-1 acts through both peripheral and central mechanisms to regulate energy homeostasis and the hedonic components of food intake. We and others have hypothesized that peptides that modulate feeding behavior may also regulate brain circuitry responsible for drug reward. In fact, we recently discovered that systemic administration of the GLP-1 long-lasting analogue exendin-4, which is already used clinically in the treatment of type 2 diabetes, reduces the rewarding effects of cocaine in mice. Within the brain, GLP-1Rs are expressed within the hypothalamus, ventral tegmental area, and nucleus accumbens, but are especially enriched in the lateral septum (LS). The LS is (re)emerging as a crucial brain region involved in the hedonic properties of psychostimulants. In the current application, we will first define cellular heterogeneity in GLP-1 receptor expression patterns within the LS and test the hypothesis that GLP-1Rs modulate dopamine neurotransmission and signaling within the LS (Aim 1). These studies will use modern molecular neuroanatomical, biochemical and electrochemical methods. Next, we will test the hypothesis that local GLP-1 receptor signaling within the LS mediates the therapeutic effects of systemic exendin-4 on cocaine reward (Aim 2). We will also examine cocaine- and GLP-1 receptor agonist-induced changes in cellular activation. Our studies will use both pharmacological and genetic approaches, taking advantage of a recently created GLP-1R conditional knockout mouse. These multidisciplinary studies will provide essential foundational knowledge of the role of the GLP-1 receptor in psychostimulant abuse. The commercial availability of several FDA-approved GLP-1 agonists for the treatment of diabetes offers readily translational opportunities to improve human outcomes in psychostimulant abuse.

描述（由申请人提供）：精神兴奋剂滥用和成瘾是一个严重的公共卫生问题。我们的实验室已开始破译胰高血糖素样肽 1 (GLP-1) 受体 (GLP-1R) 刺激对突触前多巴胺转运蛋白的多巴胺摄取、清除和运输的功能影响。 GLP-1 是一种肠促胰岛素激素和神经肽，根据食物摄入而释放。 GLP-1 通过外周和中枢机制发挥作用，调节能量稳态和食物摄入的享乐成分。我们和其他人假设调节进食行为的肽也可能调节负责药物奖励的大脑回路。事实上，我们最近发现，已在临床上用于治疗 2 型糖尿病的 GLP-1 长效类似物 exendin-4 的全身给药会降低可卡因对小鼠的奖励作用。在大脑中，GLP-1R 在下丘脑、腹侧被盖区和伏隔核中表达，但在侧中隔 (LS) 中尤其丰富。 LS 正在（重新）成为与精神兴奋剂的享乐特性相关的关键大脑区域。在当前的应用中，我们将首先定义 LS 内 GLP-1 受体表达模式的细胞异质性，并测试 GLP-1R 调节 LS 内多巴胺神经传递和信号传导的假设（目标 1）。这些研究将使用现代分子神经解剖学、生物化学和电化学方法。接下来，我们将检验以下假设：LS 内的局部 GLP-1 受体信号传导介导全身 Exendin-4 对可卡因奖赏的治疗作用（目标 2）。我们还将检查可卡因和 GLP-1 受体激动剂诱导的细胞激活变化。我们的研究将利用药理学和遗传学方法，利用最近创建的 GLP-1R 条件敲除小鼠。这些多学科研究将为 GLP-1 受体在精神兴奋剂滥用中的作用提供必要的基础知识。 FDA 批准的几种用于治疗糖尿病的 GLP-1 激动剂的商业可用性为改善人类精神兴奋剂滥用的结果提供了易于转化的机会。