Insulin mechanisms of diabetes-evoked enhancement of nicotine reward

 描述(申请人提供)：吸烟和患有糖尿病的人经历死亡和各种负面健康后果的可能性是不吸烟者的两倍。由于血管并发症的发生率较高，患有糖尿病的吸烟者的医疗费用比不吸烟的糖尿病患者高出300%。一些临床证据表明，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，吸烟并患有糖尿病的人戒烟的可能性较小，而且更担心戒烟后体重增加。其次，在糖尿病吸烟者中戒烟率最低，他们在戒烟期间也表现出高抑郁和焦虑的比率。最后，尽管普通人群的吸烟率大幅下降，但自1994年以来，糖尿病患者的吸烟率保持稳定。我们之前已经证明尼古丁的奖赏效应在链脲佐菌素和高脂饮食诱导的糖尿病大鼠中被放大。此外，糖尿病大鼠表现出多巴胺能系统受到抑制，因为伏隔核内基础和尼古丁诱发的多巴胺释放减弱，同时多巴胺D1受体减少。这些发现导致了我们的假设，即干扰糖尿病产生的胰岛素信号，改变中脑边缘系统，放大尼古丁的奖励效应。因此，这项应用的目的是确定胰岛素是否调节中脑边缘奖赏过程，从而有利于促进尼古丁的奖赏效应。为此，我们将通过在1型和2型糖尿病啮齿动物模型中补充胰岛素来检验尼古丁对糖尿病状态正常化的奖励作用。我们还将研究尼古丁对糖尿病动物的奖励效应，这些动物的胰岛素信号在中脑边缘奖励回路中得到了补偿。在我们的实验中，我们将通过测量伏隔核多巴胺释放以及测量参与奖励处理的受体和关键信号分子(如DARPP-32和AKT)来检查中脑边缘奖赏回路。我们的结果将提供有关胰岛素在调节代谢紊乱(如糖尿病)产生的尼古丁奖赏效应中的作用的重要信息。我们的发现还将说明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吸烟的风险。

 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.