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.

项目摘要 烟草的使用仍然是一个实质性的公共卫生问题，联合有1600万人 患有与烟草有关的疾病的州。虽然目前有七个尼古丁停止 食品药品监督管理局批准的药物治疗，尼古丁戒烟成功率仍然 低的。 Varenicline被认为是估计为26％的戒烟成功率最有效的治疗方法。 大多数吸烟者都报告渴望戒烟，但即使在当前的治疗中，大多数都没有成功 在他们的尝试中。随着烟草的有害健康影响以及吸烟者渴望之间的当前差异 以及戒烟的能力，对新型尼古丁成瘾治疗的研究对于改善公众至关重要 健康。最近的一项研究强调了一种新型的内源性化合物，证明了作为尼古丁停止的前景 在尼古丁奖励和戒断的鼠模型中进行处理。遵循烟草吸烟者的报告 谁遭受缺血性损伤，其岛状皮质报告报告降低了渴望和戒断较少 与其他大脑区域受伤的吸烟者相比，症状是轻度创伤性脑损伤的小鼠模型 在模型中，n- 在岛状皮质中发现烯烃（Olgly）被发现增加。除了吸烟者的报告 使用缺血性中风，其他人类成像和动物研究表明，岛状皮质在药物中起作用 成瘾，渴望和寻求。随后，N-酰基氨基酸的外源给药，Olgly， 通过过氧化物组增殖物激活尼古丁诱导的条件偏好（CPP） 受体α（PPAR-α）依赖机制和改善的甲酰胺胺预应的尼古丁 在鼠标模型中提取。在这里，我们假设：外源性olgly降低了尼古丁的寻求行为 通过在岛状皮质中的直接作用，达到达梅尼古丁诱导的多巴胺释放。 AIM 1将确定 如果岛状皮质对于奥尔格利（Olgly）和重复尼古丁（Nicotine）的尼古丁寻求行为至关重要 暴露于岛状皮质中的Olgly失调。 AIM 2将利用体内G蛋白偶联受体多巴胺 传感器要研究Olgly是否会减少伏隔核中尼古丁诱导的多巴胺释放。 拟议的研究的完成将导致对神经底物和基础的了解增加 Olgly寻求尼古丁寻求尼古丁的作用机制以及Olgly在 尼古丁成瘾。