Insulin mechanisms of diabetes-evoked enhancement of nicotine reward

糖尿病引起尼古丁奖赏增强的胰岛素机制

基本信息

批准号：
9238041
负责人：
Arbi Nazarian
金额：
$ 10万
依托单位：
WESTERN UNIVERSITY OF HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-05 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9238041
关键词：
Abstinence Animals Anxiety Blood Vessels Brain Clinical Complex DARPP Data Diabetes Mellitus Dopamine Dopamine D1 Receptor Dopamine Receptor Down-Regulation Epidemic Exhibits Gene Transfer General Population Goals Health Health Care Costs High Fat Diet IRS2 gene Individual Insulin Insulin Receptor Laboratories Light Measurement Measures Mediating Mediator of activation protein Medical Care Costs Mental Depression Metabolic Diseases Microdialysis Molecular Nicotine Nicotine Dependence Nucleus Accumbens Outcome Pathology Pathway interactions Peripheral Persons Phosphorylation Predisposition Procedures Proto-Oncogene Proteins c-akt Rattus Regulation Resistance Rewards Risk Rodent Model Role Signaling Molecule Smoke Smoker Smoking Streptozocin Supplementation System Tobacco Dependence Tobacco Use Cessation Tobacco use Up-Regulation Ventral Tegmental Area Viral Vulnerable Populations Weight Gain diabetic diabetic patient diabetic rat experience insulin signaling mesolimbic system molecular marker mortality neurobiological mechanism neurochemistry non-diabetic non-smoker non-smoking receptor relating to nervous system research study reward circuitry reward processing smoking cessation synergism tobacco abuse type I and type II diabetes

项目摘要

DESCRIPTION (provided by applicant): People who smoke and are diabetic are twice as likely to experience mortality and various negative health outcomes versus non-smokers. The health care costs of smokers that are diabetic are 300% higher than non- smoking diabetics, due to higher rates of vascular complications. Several lines of clinical evidence suggest that diabetic patients may be more susceptible to tobacco abuse. First, people who smoke and have diabetes are less likely to quit smoking and are more concerned about weight gain if they quit as compared to non- diabetic smokers. Second, tobacco cessation rates are lowest among diabetic smokers who also display high rates of depression and anxiety during abstinence. Lastly, the rates of smoking among individuals with diabetes have remained stable since 1994 despite a significant decrease in smoking rates in the general population. We have previously demonstrated that the rewarding effects of nicotine are magnified in streptozotocin- and high-fat diet-induced diabetic rats. Moreover, diabetic rats exhibit suppressed dopaminergic system by having blunted basal and nicotine-evoked dopamine release in the nucleus accumbens, along with a reduction in dopamine D1 receptors. These findings have led to our hypothesis that disrupted insulin signaling, produced by diabetes, alters the mesolimbic system to magnify the rewarding effects of nicotine. Therefore, the goal of this application is to determine whether insulin modulates mesolimbic reward processing in favor of promoting the rewarding effects of nicotine. To that end, we will examine the rewarding effects of nicotine upon normalizing the diabetic state by supplementing insulin in rodent models of Type 1 and Type 2 diabetes. We will also examine the reward effects of nicotine in diabetic animals whose insulin signaling has been compensated within the mesolimbic reward circuitry. The mesolimbic reward circuitry will be examined in our experiments by measurement of nucleus accumbens dopamine release and measurement of receptors and key signaling molecules (e.g. DARPP-32 and AKT) involved in reward processing. Our results will provide important information regarding the role of insulin in modulating the rewarding effects of nicotine produced by metabolic disorders, such as diabetes. Our findings will also speak to the efficacy of insulin therapy used to treat diabetes and whether these therapies can reduce the risk of tobacco use.

描述（由适用提供）：吸烟和糖尿病患者的死亡率和各种负面健康结果的可能性是与非吸烟者的两倍。由于血管并发症发生率更高，糖尿病吸烟者的医疗保健费用比非吸烟糖尿病患者高300％。几条临床证据表明，糖尿病患者可能更容易受到烟草滥用的影响。首先，与非糖尿病吸烟者相比，吸烟和患有糖尿病的人戒烟的可能性较小，并且更担心体重增加。其次，糖尿病吸烟者的烟草戒烟率最低，他们在禁欲期间也表现出高抑郁症和焦虑症。最后，自1994年以来，尽管普通人群的吸烟率显着降低，但糖尿病患者的吸烟率一直保持稳定。我们先前已经证明，尼古丁在链蛋白酶饮食诱导的糖尿病大鼠中的奖励作用被放大。此外，糖尿病大鼠通过在伏伏核中钝化了基本和尼古丁诱发的多巴胺释放，并减少了多巴胺D1受体，从而抑制了多巴胺能系统。这些发现导致了我们的假设，即糖尿病产生的胰岛素信号传导破坏了糖尿病，从而改变了中唇系统，以放大尼古丁的奖励作用。因此，本应用的目的是确定胰岛素是否调节中唇奖励处理，以促进尼古丁的奖励作用。为此，我们将通过补充1型和2型糖尿病的啮齿动物模型中的胰岛素来检查尼古丁对糖尿病状态归一化的奖励作用。我们还将检查尼古丁在糖尿病动物中的奖励作用，这些糖尿病动物的胰岛素信号在中唇奖励电路中得到了补偿。在我们的实验中，将检查中左右的奖励电路，通过测量伏巴核的核释放和接收器的测量以及涉及奖励处理的关键信号分子（例如DARPP-32和AKT）的测量。我们的结果将提供有关胰岛素在调节代谢性疾病（例如糖尿病）产生的尼古丁的奖励作用中的作用的重要信息。我们的发现还将谈到用于治疗糖尿病的胰岛素疗法的有效性，以及这些疗法是否可以降低烟草使用的风险。