Understanding the role of dopamine antagonists on peripheral glucose regulation

多巴胺是大脑中主要的神经递质之一。多巴胺神经元的细胞核存在于中脑，该区域的神经元将其轴突投射到大脑前半部分的大部分区域。多巴胺调节各种各样的行为，包括运动和动机行为，在记忆和注意力中具有额外的作用。多巴胺的神经元受体主要有两种类型：D1和D2型受体。用拮抗剂阻断多巴胺D2受体对运动和行为有很好的表征作用，并产生减少的运动活性。然而，我们和其他人最近已经证明，中枢作用的D2拮抗剂，以及阻断D2和5-羟色胺5-HT 2A受体的药物，也对外周葡萄糖调节具有有效作用，导致葡萄糖水平增加和全身胰岛素抵抗。其机制仍不完全清楚，因为大脑外的D2受体相对较少，这表明这是一种对葡萄糖代谢具有潜在重要性的间接途径。 我们的研究表明，这种现象可能是通过增加外周儿茶酚胺（去甲肾上腺素，肾上腺素，可能多巴胺），我们已经测量后D2和D2/5-HT 2A拮抗剂治疗介导的。目前，本提案将扩展我们先前在这一领域发表的研究，并通过直接修饰外周儿茶酚胺（主要是去甲肾上腺素和肾上腺素）来验证我们的假设，即这些激素起着关键作用，从而有助于阐明这些发现。在三个主要目标中，我们将试图证实这些药物的葡萄糖调节是通过外周儿茶酚胺介导的。在第一个目标中，我们将通过手术切除大鼠的肾上腺，这将防止肾上腺素的增加，并使用高胰岛素-正葡萄糖钳夹评估全身胰岛素敏感性。在第二个主要目标中，将用利血平药物预处理单独的大鼠组，利血平药物导致囊泡储存中去甲肾上腺素的持久消耗。预计这种药理学操作可以阻断我们在用D2和D2/5-HT 2A拮抗剂治疗时观察到的儿茶酚胺释放的增加，从而改善D2和D2/5-HT 2A拮抗剂对外周葡萄糖调节和胰岛素敏感性的影响。最后，在第三个目标，我们将确认这些药物的初始效果介导的中央，而不是外周，通过给药他们通过脑室内插管，并观察外周儿茶酚胺水平和葡萄糖浓度的影响。为此，还将通过免疫组织化学研究动物的c-fos（一种神经活动的测量方法），以确定哪些脑区可能负责启动下游代谢效应的激活。

Dopamine represents one of the major neurotransmitters in the brain. The cell nuclei for dopamine neurons exist in the midbrain, and the neurons in this region project their axons throughout much of the frontal half of the brain. Dopamine modulates a wide variety of behaviors, including movement and motivated behaviors, with additional roles in memory and attention. There are two main types of neuronal receptor for dopamine: the D1 and D2 type receptors. Blocking dopamine D2 receptors with an antagonist has well characterized effects on movement and behavior, and produces decreased locomotor activity. However, we and others have recently demonstrated that centrally acting D2 antagonists, as well as drugs that block both the D2 and serotonin 5-HT2A receptor, also have a potent effect on peripheral glucose regulation, causing increases in glucose levels and whole-body insulin resistance. The mechanism for this remains incompletely known, as there are relatively few D2 receptors outside of the brain suggesting an indirect pathway of potential importance to glucose metabolism. Our research indicates that this phenomenon may be mediated through increases in peripheral catecholamines (norepinephrine, epinephrine, and possibly dopamine), which we have measured after D2 and D2/5-HT2A antagonist treatment. Presently, the current proposal will extend our prior published studies in this area and help to elucidate these findings by directly modifying peripheral catecholamines (primarily norepinephrine and epinephrine) to test our hypothesis that these hormones play a critical role. In three main aims, we will seek to confirm that glucose regulation by these drugs is mediated through peripheral catecholamines. In the first aim, we will surgically remove the adrenal glands of rats, which will prevent increases in epinephrine, and assess whole body insulin sensitivity using the hyperinsulinemic-euglycemic clamp. In the second main aim, separate groups of rats will be pretreated with the drug reserpine, which causes a lasting depletion of norepinephrine from vesicular stores. This pharmacological manipulation is predicted to block the increases in catecholamine release we observe when treated with D2 and D2/5-HT2A antagonists, and consequently ameliorate the effects of the D2 and D2/5-HT2A antagonists on peripheral glucose regulation and insulin sensitivity. Finally, in the third aim, we will confirm that the initial effects of these drugs are mediated centrally, rather than peripherally, by administering them centrally through an intracerebroventricular cannula, and observing the effects on peripheral catecholamine levels and glucose concentrations. Animals in this aim will also be studied via immunohistochemistry for c-fos (a measure of neural activity) to determine which brain regions may be responsible for initiating the activation of the downstream metabolic effects.