Understanding the role of dopamine antagonists on peripheral glucose regulation

点击翻译按钮获取中文摘要

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.