GLP-1 Receptors and Psychostimulant Addiction

GLP-1 受体和精神兴奋剂成瘾

基本信息

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
项目类别：
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

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

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项目摘要

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）：精神刺激滥用和成瘾是一个严重的公共卫生问题。我们的实验室已经开始破译胰高血糖素样肽1（GLP-1）受体（GLP-1R）刺激对多巴胺摄取，清除和流行性多巴胺转运蛋白的运输的功能作用。 GLP-1是一种肠降血糖素激素和神经肽，响应食物摄入而释放。 GLP-1通过外围和中央机制起作用，调节能量稳态和食物摄入的享乐分量。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脑电路。实际上，我们最近发现，GLP-1长期类似物Exendin-4的全身性给药已在临床治疗2型糖尿病治疗中，从而降低了可卡因对小鼠的奖励作用。在大脑内，GLP-1R在下丘脑，腹侧盖区域和伏隔核中表达，但在侧隔隔（LS）中尤其富集。 LS是（重新）作为参与精神刺激物的享乐特性的关键大脑区域。在当前应用中，我们将首先定义LS中GLP-1受体表达模式中的细胞异质性，并检验GLP-1RS在LS内调节多巴胺神经传递和信号传导的假设（AIM 1）。这些研究将使用现代的分子神经解剖学，生化和电化学方法。接下来，我们将检验以下假设：LS中的局部GLP-1受体信号传导介导全身exendin-4对可卡因奖励的治疗作用（AIM 2）。我们还将检查可卡因和GLP-1受体激动剂引起的细胞活化变化。我们的研究将利用最近创建的GLP-1R条件敲除小鼠使用药理和遗传方法。这些多学科研究将为GLP-1受体在精神刺激滥用中的作用提供基本知识。几种经FDA批准的GLP-1激动剂的商业可用性可用于治疗糖尿病，这为改善精神刺激滥用的人类结果提供了容易的转化机会。