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

项目摘要 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。 患有烟草相关疾病的州。虽然目前有七种尼古丁戒烟方法 尽管美国食品和药物管理局批准的药物疗法中，尼古丁戒断成功率仍然保持不变， 低伐尼克兰被认为是最有效的治疗方法，估计戒烟成功率为26%。 大多数吸烟者都有戒烟的愿望，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。随着烟草对健康的有害影响以及吸烟者对烟草的需求 和戒烟的能力，研究新的尼古丁成瘾治疗是至关重要的，以改善公众 健康最近的一项研究强调了一种新的内源性化合物，证明有希望作为尼古丁戒烟 尼古丁奖赏和戒断的鼠模型中的治疗。在一份报告中， 岛叶皮层持续缺血性损伤的人报告说， 症状相比，吸烟者与其他脑区损伤，轻度创伤性脑损伤小鼠模型 被用来确定可能抵消尼古丁奖励和依赖的神经化学物质。在模型中，n- 发现油酰甘氨酸（OlGly）在岛叶皮层中增加。除了吸烟者的报告外， 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作用， 上瘾，渴望，和寻求。随后，外源性给予N-酰基氨基酸OlGly， 防止尼古丁诱导的条件性位置偏爱（CPP）通过过氧化物酶体增殖物激活 受体α（PPAR-α）依赖性机制和改善的美加明沉淀尼古丁 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 通过直接作用于岛叶皮层来抑制尼古丁诱导的多巴胺释放。目标1将决定 如果岛叶皮层对于OlGly引起的尼古丁寻求行为的衰减至关重要， 暴露会使岛叶皮质中的OlGly失调。目的2将利用体内G蛋白偶联受体多巴胺 传感器，以研究OlGly是否减少尼古丁诱导的多巴胺释放在延髓核。 完成拟议的研究将导致增加对神经基质和基础的理解。 参与OlGly减弱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.