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.
Persons with diabetes who smoke are less likely to quit and appear to be more susceptible to tobacco abuse. Previous studies in our laboratory have shown that the pleasurable (rewarding) effects of nicotine are enhanced in rodent models of Type 1 and Type 2 diabetes. However, a critical unanswered question is whether disruptions in insulin signaling act to enhance the rewarding effects of nicotine during diabetes. Our project is set to determine whether normalization of the diabetic state and changes in insulin signaling in the brain will reduce the enhanced pleasurable effects of nicotine. The findings from this project will shed light on neurobiological mechanisms by which persons with diabetes have a greater vulnerability to tobacco use. The long-term goal of this project is to identify ways by which control and treatment of metabolic disorders can assist in facilitating nicotine cessation in persons who smoke and are diabetic.
| Íbias, Javier; O'Dell, Laura E; Nazarian, Arbi (2018) Insulin dependent and independent normalization of blood glucose levels reduces the enhanced rewarding effects of nicotine in a rodent model of diabetes. Behav Brain Res 351:75-82 |
| Pipkin, Joseph A; Cruz, Bryan; Flores, Rodolfo J et al. (2017) Both nicotine reward and withdrawal are enhanced in a rodent model of diabetes. Psychopharmacology (Berl) 234:1615-1622 |
