GLP-1 Receptors and Psychostimulant Addiction

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。我们的实验室已经开始破译胰高血糖素样肽1（GLP-1）受体（GLP-1 R）刺激对多巴胺摄取、清除和突触前多巴胺转运蛋白运输的功能影响。GLP-1是一种肠促胰岛素激素和神经肽，在食物摄入后释放。GLP-1通过外周和中枢机制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，全身给予GLP-1长效类似物exendin-4（已在临床上用于治疗2型糖尿病）可降低可卡因对小鼠的奖励作用。在脑内，GLP-1 R在下丘脑、腹侧被盖区和丘脑核内表达，但在外侧隔（LS）中尤其富集。LS正在（重新）成为一个重要的大脑区域，参与精神兴奋剂的享乐特性。在本申请中，我们将首先定义LS内GLP-1受体表达模式的细胞异质性，并检验GLP-1 R调节LS内多巴胺神经传递和信号传导的假设（目的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LS内的局部GLP-1受体信号传导介导全身性毒蜥外泌肽-4对可卡因奖赏的治疗作用的假设（目的2）。我们还将研究可卡因和GLP-1受体激动剂诱导的细胞活化变化。我们的研究将使用药理学和遗传学方法，利用最近创建的GLP-1 R条件性敲除小鼠。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。几种FDA批准的用于治疗糖尿病的GLP-1激动剂的商业可用性为改善精神兴奋剂滥用的人类结局提供了容易转化的机会。

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.