Lipid biosignatures of drug addiction

描述(由申请人提供)：我们假设成瘾药物改变了大脑和周围组织中的细胞脂质通路，并且这种改变影响了向强制药物使用的转变。这一想法的推论是，外周脂质变化可能被用作成瘾的生物标记物或生物标志(复合生物标记物)。我们实验的目的是通过对脂体的公正评估，发现可能与大鼠甲基苯丙胺自我给药有关的脂质功能异常(人类成瘾的模型)，并确定可能用于筛选暴露和成瘾易感性的外周生物标志物候选。为了实现这一目标，我们将从获得甲基苯丙胺自我给药和随后戒毒的不同阶段的大鼠身上提取组织样本。然后，我们将使用液相色谱/质谱仪对样品进行脂类分析。最后，我们将处理所获得的信息，并将其与行为和分子数据相结合，以产生关于新描述的脂质异常的功能意义的可检验假说。初步实验发现，暴露于甲基苯丙胺的大鼠脑和肝脏组织中存在多种脂质变化。我们有两个具体目标。目的1：发现自我给予甲基苯丙胺的大鼠脑内脂体异常。我们将(I)描述在获得甲基苯丙胺自我给药和随后的戒毒过程中大脑脂体的情况；(Ii)探索我们的脂类工作发现的显著脂质变化的潜在机制；(Iii)测试这种变化是否与药物自我给药相关；以及(Iv)研究当甲基苯丙胺自我给药从随意、控制使用发展到强制摄入时，是否可以用脂质异常来监测成瘾的严重程度。目的2：发现甲基苯丙胺暴露大鼠外周组织中的脂类异常，寻找甲基苯丙胺暴露的候选生物标志物。我们将扩展在目标1中进行的脂肪组学分析，以包括易于进行活组织检查和/或与大脑(血液、骨骼肌、皮下脂肪、皮肤)代谢相互作用的外围组织。我们还将确定外周血脂谱的预先存在的差异是否会使大鼠倾向于发展强迫性成瘾行为，从而潜在地作为甲基苯丙胺成瘾的先行生物标志物。为了发现与药物自我给药相关的异常，对脂体进行系统和公正的研究还有待尝试。拟议的研究解决了这一差距，如果成功，将导致发现新的成瘾候选生物标记物。这项工作将保留7个现有工作岗位，并创造4个新的工作岗位。公共卫生相关性：我们建议对大鼠不同组织中的所有脂类进行系统和公正的研究，以确定与甲基苯丙胺成瘾相关的异常，并发现这种疾病的早期生物标志物。

DESCRIPTION (provided by applicant): We hypothesize that addictive drugs alter cellular lipid pathways in brain and peripheral tissues, and that such alterations influence the transition to compulsive drug use. A corollary of this idea is that peripheral lipid alterations might be used as biomarkers or biosignatures (composite biomarkers) of addiction. The goal of our experiments is to discover, through an unbiased evaluation of the lipidome, abnormalities in lipid function that might be involved in methamphetamine self-administration in rats (a model for human addiction) and identify peripheral biomarker candidates that might be used to screen for exposure and vulnerability to addiction. To achieve this goal, we will take tissue samples from rats at different stages of acquisition of methamphetamine self-administration and subsequent abstinence from the drug. We will then conduct lipidome-wide analyses of the samples using liquid chromatography/mass spectrometry. Finally, we will process the information obtained and integrate it with behavioral and molecular data to generate testable hypotheses on the functional significance of newly described lipid abnormalities. Initial experiments have uncovered multiple lipid alterations in brain and liver tissues from methamphetamine-exposed rats. We have two specific aims. Aim 1: To discover lipidomic abnormalities in the brain of rats that self-administer methamphetamine. We will (i) profile the brain lipidome during the acquisition of methamphetamine self-administration and subsequent abstinence from the drug; (ii) explore the mechanisms underlying significant lipid alterations uncovered by our lipidomic work; (iii) test whether such alterations correlate with drug self- administration; and (iv) examine whether lipid abnormalities might be used to monitor the severity of addiction as methamphetamine self-administration progresses from casual, controlled use to compulsive intake in susceptible individuals. Aim 2: To discover lipidomic abnormalities in peripheral tissues of rats exposed to methamphetamine, and identify candidate biomarkers for methamphetamine exposure. We will extend the lipidomic analyses conducted in Aim 1 to include peripheral tissues that are readily accessible to biopsy and/or interact metabolically with the brain (blood, skeletal muscle, subcutaneous fat, skin). We will also determine whether pre-existing differences in peripheral lipid profiles may predispose rats toward developing compulsive addiction-like behavior, and thus be potentially useful as antecedent biomarkers for methamphetamine addiction. A systematic and unbiased search of the lipidome to discover abnormalities associated with drug self- administration has yet to be attempted. The proposed studies address this gap and will result, if successful, in the discovery of novel biomarker candidates for addiction. This work will result in the retention of 7 existing jobs and the creation of 4 new jobs. PUBLIC HEALTH RELEVANCE: We propose to conduct a systematic and unbiased search of all lipids (the 'lipidome') in various rat tissues to identify abnormalities associated with methamphetamine addiction and discover early biomarkers for this disease.