GLP-1 Receptor Signaling, Dopamine Homeostasis and Psychostimulant Abuse

描述(由申请人提供)：精神刺激性滥用和上瘾是个人遭受严重痛苦的原因，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疗法。可卡因和安非他明等精神刺激剂劫持了多巴胺(DA)奖励通路，导致突触DA升高。新的数据表明，胰高血糖素样肽-1(GLP-1)受体(GLP-1R)参与调节这些药物奖赏回路的成分。GLP-1是一种激素和神经肽，由肠道中的L细胞根据食物的摄入而释放，通过外周和中枢机制调节能量平衡和摄食行为。已有研究表明，激活中脑边缘GLP-1RS可减少高口感食物的摄入量，提示GLP-1R信号调节食物摄取的享乐成分以及可能的奖赏过程。我们最近发现，全身应用一种长效的GLP-1类似物(exendin-4或Ex-4)，可以减弱可卡因对小鼠的奖赏效应。EX-4还可以减少苯丙胺诱导的大鼠的运动活动。重要的是，GLP-1Rs在下丘脑、腹侧被盖区(VTA)和伏核表达，但尤其在外侧隔(LS)表达。众所周知，LS接受来自VTA的多巴胺能输入，VTA是精神刺激药物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，我们将检验GLP-1R激活调节LS内DA神经传递和信号的主要假说。重要的是，我们假设这一规定削弱了精神刺激剂的回报效应。为了确定LS中DA神经传递的功能调节，我们将首先测量刺激GLP-1R对DA摄取和清除的影响，以及对突触前DA转运体(DAT)和DA D2受体的运输的影响，这两个受体是精神刺激剂的分子靶点(目标1)。接下来，我们将评估LS内的局部GLP-1R信号是否介导了全身性Ex-4对可卡因奖励的治疗效果(目标2)。最后，我们建议确定LS内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(目标3)。这些实验将确定GLP-1信号在调节精神刺激剂的奖赏特性中的作用。由于这项研究采取了机械论的方法，其发现有可能导致各种奖励功能障碍，包括药物奖励和食物奖励。值得注意的是，GLP-1长效类似物已经获得FDA批准，并已上市用于治疗糖尿病；因此，这些发现可能很容易转化为治疗精神刺激性药物滥用。

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.