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: 10649472
• 负责人: Kimberly Nicole Karin
• 金额: $ 1.27万
• 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 2023-11-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10649472
• 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; Disparity; 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; Pharmacotherapy; 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; brain tissue; conditioned place preference; craving; effective therapy; human imaging; improved; in vivo; ischemic injury; male; mild traumatic brain injury; mouse model; neural; neurochemistry; neurotransmitter release; nicotine cessation; nicotine exposure; nicotine replacement; nicotine reward; nicotine seeking behavior; nicotine self-administration; novel; pharmacologic; pre-clinical; preclinical study; prevent; programs; putamen; 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.

项目总结

项目成果

Investigation of Cannabidiol in the Mouse Drug Discrimination Paradigm.

小鼠药物歧视范式中大麻二酚的研究。

• DOI: 10.1089/can.2022.0198
• 发表时间: 2024
• 期刊: Cannabis and cannabinoid research
• 影响因子: 3.8
• 作者: Mustafa,MohammedA;Poklis,JustinL;Karin,KimberlyN;Elmer,JaydenA;Porter,JosephH;Parra,Victoria;Lu,Dai;Schlosburg,JoelE;Lichtman,AronH
• 通讯作者: Lichtman,AronH