Oleoyl Glycine-induced reduction of Nicotine Seeking: Bioanalytical & Behavioral Approaches

项目总结 烟草使用仍然是一个重大的公共卫生问题，在美国有1600多万人 患有与烟草有关的疾病的国家。虽然目前有七个尼古丁戒除者 美国食品和药物管理局批准的药物疗法，尼古丁戒断成功率保持不变 很低。Varenicline被认为是最有效的治疗方法，戒断成功率估计为26%。 大多数吸烟者报告有戒烟的愿望，但即使采用目前的治疗方法，大多数也不成功。 在他们的尝试中。由于烟草对健康的有害影响和目前吸烟者的愿望之间的差距 和戒烟能力，研究新的尼古丁成瘾治疗方法对于提高公众 健康。最近的一项研究强调了一种新的内源性化合物，它显示出戒烟的前景 尼古丁奖赏和戒断小鼠模型的治疗。在一份报告中，吸烟者 遭受岛叶皮质缺血性损伤的世卫组织报告说，他们的渴求减少了，戒断症状也不那么严重 症状与吸烟者有其他脑区损伤的小鼠相比，轻度创伤性脑损伤的模型 被用来识别可能抵消尼古丁奖励和依赖的神经化学物质。在模型中，n- 在岛叶皮质中发现油酰甘氨酸(OlGly)增加。除了在吸烟者中的报告 对于缺血性中风，其他人类成像和动物研究表明，岛叶皮质在药物治疗中发挥了作用 上瘾、渴求和寻觅。随后，外源性给予N-酰基氨基酸OlGly， 通过过氧化物酶体增殖物激活抑制尼古丁诱导的条件性位置偏爱 受体α(PPAR-α)依赖机制及改善甲氨基甲胺沉淀的尼古丁 小鼠模型中的戒断反应。在这里，我们假设：外源性OlGly减少尼古丁寻求行为 通过在岛叶皮质的直接作用来抑制尼古丁诱导的多巴胺释放。目标一号将决定 如果岛叶皮质对OlGly减弱尼古丁寻求行为至关重要，如果尼古丁重复使用 暴露会扰乱岛叶皮质中的OlGly。AIM 2将利用体内G蛋白偶联受体多巴胺 研究OlGly是否减少尼古丁诱导的伏隔核多巴胺释放。 拟议研究的完成将导致对神经底物和潜在的 OlGly抑制尼古丁寻求的作用机制以及OlGly在 尼古丁成瘾。

PROJECT SUMMARY Tobacco use continues to be a substantial public health issue with more than 16 million individuals in the United States suffering from a tobacco-related disease. While there are currently seven nicotine cessation pharmacotherapies approved by the Food and Drug Administration, nicotine cessation success rates remain low. Varenicline is considered to be the most effective treatment with a cessation success rate estimated at 26%. A majority of smokers report a desire to quit smoking, and yet even with current treatments most are unsuccessful in their attempts. With the deleterious health effects of tobacco and the current disparity between smokers’ desire and ability to quit smoking, research into novel nicotine addiction treatments is critical for improvement of public health. A recent study highlighted a novel endogenous compound demonstrating promise as a nicotine cessation treatment in murine models of nicotine reward and withdrawal. Following a report in which tobacco smokers who sustained ischemic injury to their insular cortex reported reduced craving and less severe withdrawal symptoms compared to smokers with injury to other brain areas, a mouse model of mild traumatic brain injury was employed to identify neurochemicals that may offset nicotine reward and dependence. In the model, n- oleoyl glycine (OlGly) was discovered to be increased in the insular cortex. In addition to the report in smokers with ischemic stroke, other human imaging and animal studies suggest the insular cortex plays a role in drug addiction, craving, and seeking. Subsequently, exogenous administration of the n-acyl amino acid, OlGly, prevented nicotine-induced conditioned place preference (CPP) through a peroxisome proliferator-activated receptor alpha (PPAR-α) dependent mechanism and ameliorated mecamylamine-precipitated nicotine withdrawal in mouse models. Here, we hypothesize: exogenous OlGly reduces nicotine seeking behavior through direct actions in the insular cortex to dampen nicotine-induced dopamine release. Aim 1 will determine if the insular cortex is critical for the attenuation of nicotine seeking behavior by OlGly and if repeated nicotine exposure dysregulates OlGly in the insular cortex. Aim 2 will utilize in vivo G-protein coupled receptor dopamine sensors to investigate whether OlGly reduces nicotine-induced dopamine release in the nucleus accumbens. Completion of the proposed research will lead to an increased understanding of neural substrates and underlying mechanisms of action involved in the attenuation of nicotine seeking by OlGly, as well as the role of OlGly in nicotine addiction.