GLP-1 Receptor Signaling, Dopamine Homeostasis and Psychostimulant Abuse

描述（由申请人提供）：精神兴奋剂滥用和成瘾是导致个人强烈痛苦的原因，是一个主要的公共卫生问题。然而，几乎没有治疗这些毁灭性疾病的方法。可卡因和安非他明等精神兴奋剂劫持多巴胺（DA）奖赏通路，导致突触DA升高。新出现的数据暗示胰高血糖素样肽-1 （GLP-1）受体（GLP-1R）在这些药物奖励回路的调节成分中。GLP-1是一种激素和神经肽，由肠道l细胞在食物摄入时释放，并通过外周和中枢机制调节能量稳态和摄食行为。研究表明，中脑边缘GLP-1Rs的激活减少了美味食物的摄入，这表明GLP-1R信号调节了食物摄入的享乐成分，可能还调节了奖励过程。我们最近发现，全身长期服用GLP-1类似物（exendin-4或Ex-4）会减弱小鼠体内可卡因的奖励作用。Ex-4还能减少安非他明引起的大鼠运动活动。重要的是，GLP-1Rs在下丘脑、腹侧被盖区（VTA）和伏隔核中表达，但在外侧隔（LS）中尤其富集。众所周知，左系神经接收来自VTA的多巴胺能输入，这是精神兴奋剂滥用的一个重要区域，但对该区域DA神经传递的调节知之甚少。在本研究中，我们将验证GLP-1R激活调节DA神经传递和LS内信号传导的总体假设。重要的是，我们假设这种调节减弱了精神兴奋剂的奖励作用。为了确定LS中DA神经传递的功能调节，我们将首先测量GLP-1R刺激对DA摄取和清除的影响，以及对突触前DA转运体（DAT）和DA D2受体（精神兴奋剂的分子靶点）运输的影响（Aim 1）。接下来，我们将评估LS内局部GLP-1R信号是否介导系统性Ex-4对可卡因奖赏的治疗作用（目的2）。最后，我们建议确定LS中GLP- 1激活神经元的细胞表型与DA神经支配和DA受体表达模式的关系（目的3）。这些实验将确定GLP-1信号在调节精神兴奋剂的奖励特性中的作用。由于本研究采用的是一种机制方法，其研究结果可能对各种奖励功能障碍，包括药物奖励和食物奖励有潜在的影响。值得注意的是，GLP-1长效类似物已经获得fda批准并上市用于治疗糖尿病；因此，这些发现可能很容易转化为精神兴奋剂药物滥用的治疗。

DESCRIPTION (provided by applicant): Psychostimulant abuse and addiction are causes of intense suffering for the individual and represent a major public health concern. Yet, few therapies exist to treat these devastating conditions. Psychostimulants like cocaine and amphetamine hijack dopamine (DA) reward pathways, leading to elevated synaptic DA. Emerging data implicate the glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) in modulating components of these drug reward circuitries. GLP-1, a hormone and neuropeptide, is released by L-cells of the intestines in response to food intake and acts through both peripheral and central mechanisms to regulate energy homeostasis and feeding behaviors. It has been shown that activation of mesolimbic GLP-1Rs decreases the intake of highly palatable foods, suggesting that GLP-1R signaling regulates the hedonic components of food intake and possibly reward processes. We have recently discovered that systemic administration of a long- lasting GLP-1 analogue (exendin-4 or Ex-4), attenuates the rewarding effects of cocaine in mice. Ex-4 also reduces amphetamine-induced locomotor activity in rats. Importantly, GLP-1Rs are expressed within the hypothalamus, ventral tegmental area (VTA), and nucleus accumbens, but are especially enriched in the lateral septum (LS). The LS is known to receive dopaminergic input from the VTA, an important area in psychostimulant abuse, but little is known about the modulation of DA neurotransmission in this area. In the present study, we will test the overarching hypothesis that GLP-1R activation modulates DA neurotransmission and signaling within the LS. Importantly, we hypothesize that this regulation blunts the rewarding effects of psychostimulants. To determine functional modulation of DA neurotransmission in the LS, we will first measure effects of GLP-1R stimulation on DA uptake and clearance, as well as on trafficking of presynaptic DA transporter (DAT) and DA D2 receptors, molecular targets of psychostimulants (Aim 1). Next, we will evaluate whether local GLP-1R signaling within the LS mediates the therapeutic effects of systemic Ex-4 on cocaine reward (Aim 2). Finally, we propose to determine the cellular phenotype of GLP- 1-activated neurons in the LS in relation to DA innervation and DA receptor expression patterns (Aim 3). These experiments will determine the role of GLP-1 signaling in regulating the rewarding properties of psychostimulants. Because this study takes a mechanistic approach, its findings have the potential to various reward dysfunctions, including drug reward and food reward. Notably, GLP-1 long-lasting analogues are already FDA-approved and on the market for the treatment of diabetes; thus these findings may be readily translatable to the treatment of psychostimulant drug abuse.