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

油酰甘氨酸诱导的尼古丁寻求减少：生物分析

• 批准号: 10537810
• 负责人: Kimberly Nicole Karin
• 金额: $ 4.07万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-25 至 2024-08-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10537810
• 关键词: Adult; Amino Acids; Amygdaloid structure; Animals; Area; Behavioral; Behavioral Assay; Biological Assay; Brain; Brain region; Bupropion; Cerebellum; Cessation of life; Chronic; Clinical Trials; Data; Disease; Dopamine; Dopamine Receptor; Drug Addiction; Drug abuse; Endocannabinoids; Female; G-Protein-Coupled Receptors; Glycine; Health; Healthcare Systems; High Pressure Liquid Chromatography; Individual; Infusion procedures; Injury; Ischemic Stroke; Lipids; Measurement; Measures; Mecamylamine; Modeling; Mus; Neuromodulator; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Nucleus Accumbens; PPAR alpha; Pharmacology; Pharmacotherapy; Play; Public Health; Rattus; Reporting; Research; Rewards; Role; Scientist; Self Administration; Sex Differences; Signaling Molecule; Smoker; Smoking; Techniques; Tobacco; Tobacco Dependence; Tobacco Use Cessation; Tobacco use; Training; United States; United States Food and Drug Administration; Ventral Tegmental Area; Withdrawal; Withdrawal Symptom; addiction; antagonist; attenuation; base; brain tissue; conditioned place preference; craving; effective therapy; human imaging; in vivo; ischemic injury; male; mild traumatic brain injury; mouse model; neurochemistry; neurotransmitter release; nicotine cessation; nicotine exposure; nicotine replacement; nicotine reward; nicotine seeking behavior; novel; pre-clinical; preclinical study; prevent; programs; putamen; relating to nervous system; sensor; smoking cessation; success; tandem mass spectrometry; tobacco smokers; varenicline

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.

项目概要 烟草使用仍然是一个重大的公共卫生问题，美国有超过 1600 万人吸烟 患有与烟草有关的疾病的国家。虽然目前有七位戒烟者 美国食品和药物管理局批准的药物疗法，尼古丁戒烟成功率保持不变 低的。 Varenicline 被认为是最有效的治疗方法，戒烟成功率估计为 26%。 大多数吸烟者表示希望戒烟，但即使采用目前的治疗方法，大多数仍不成功 在他们的尝试中。鉴于烟草对健康的有害影响以及目前吸烟者愿望之间的差距 和戒烟能力，新型尼古丁成瘾治疗方法的研究对于改善公众的戒烟能力至关重要 健康。最近的一项研究强调了一种新型内源性化合物，该化合物有望戒除尼古丁 尼古丁奖励和戒断小鼠模型的治疗。根据一份报告，吸烟者 岛叶皮质遭受缺血性损伤的人报告渴望减少且戒断症状减轻 与其他大脑区域受伤的吸烟者的症状相比，轻度创伤性脑损伤的小鼠模型 用于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- 研究发现油酰甘氨酸（OlGly）在岛叶皮质中增加。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中发挥作用 成瘾、渴望和寻求。随后，外源施用n-酰基氨基酸OlGly， 通过过氧化物酶体增殖物激活来预防尼古丁诱导的条件性位置偏好（CPP） 受体α（PPAR-α）依赖性机制和改善美加明沉淀尼古丁 小鼠模型中的戒断反应。在这里，我们假设：外源性 OlGly 会减少尼古丁寻求行为 通过直接作用于岛叶皮质来抑制尼古丁诱导的多巴胺释放。目标1将决定 岛叶皮质是否对于减弱 OlGly 寻求尼古丁的行为至关重要，以及是否重复尼古丁 暴露会使岛叶皮质中的 OlGly 失调。目标 2 将利用体内 G 蛋白偶联受体多巴胺 传感器来研究 OlGly 是否减少尼古丁诱导的伏隔核中多巴胺的释放。 完成拟议的研究将加深对神经基质和潜在机制的了解 OlGly 减弱尼古丁寻求的作用机制，以及 OlGly 在 尼古丁成瘾。