Neurochemical mechanisms governing footshock-induced suppression of methamphetamine intake

控制足部电击引起的甲基苯丙胺摄入抑制的神经化学机制

• 批准号: 10527890
• 负责人: Martin O Job
• 金额: $ 12.08万
• 依托单位: ROWAN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10527890
• 关键词: Address; Adoption; Adult; Affect; Animal Testing; Animals; Area; Behavior; Behavioral; Biochemical; Biological Assay; Brain; CARTPT gene; Cluster Analysis; Consumption; Corticotropin-Releasing Hormone; Data; Development; Dose; Epidemic; Epigenetic Process; FDA approved; Female; Foundations; Genetic; Health; Hour; Infusion procedures; Intake; Knowledge; Laboratories; Laboratory Animals; Lead; Logistic Regressions; Long-Evans Rats; Methamphetamine; Methamphetamine use disorder; Methods; Modeling; Molecular; Names; Nucleus Accumbens; Opioid Peptide; Pathway interactions; Persons; Pharmaceutical Preparations; Pharmacotherapy; Population; Protocols documentation; Punishment; Rattus; Regimen; Reproducibility; Research; Research Personnel; Resistance; Rewards; Schedule; Scientist; Self Administration; Shock; Standardization; Stress; Substance Use Disorder; Sucrose; System; Training; Work; addiction; analytical method; base; endophenotype; experimental study; footshock induced; health management; improved; male; methamphetamine abuse; methamphetamine effect; neurochemistry; novel; novel strategies; pain sensitivity; pre-clinical; psychosocial; response; tool

PROJECT SUMMARY One feature of methamphetamine use disorders (METH-UD) is that some people will continue taking METH despite negative psychosocial consequences while others will stop under the same conditions. Understanding the mechanism governing the differences between these groups will enable the development of new pharmacotherapies for METH-UD and will be important in addressing the ongoing health crisis. To model this phenomenon, scientists developed a preclinical punishment model which uses punishment conditions (e.g., increasing footshock intensity, FSI) paired with METH self-administration to differentiate shock-sensitive (SS) and shock-resistant (SR) rats. However, though widely accepted in the field, the current version of the punishment model is limited by its reliance on subjective and arbitrary endpoints to distinguish SS from SR groups and thus is limited in its robustness, reproducibility, and reliability. To address the weaknesses inherent in the current punishment protocol, we developed a novel quantitative and objective approach which we named the Quantitative Punishment Model with Clustering (QPMC). The QPMC obtains several variables from the METH taking behavior before and after the punishment regimen, followed by clustering to objectively determine distinct groups. We present preliminary data that suggests that QPMC is superior to the current punishment model with regards to identifying populations that are truly biochemically distinct. Wider adoption of QPMC will require more extensive comparisons between the two models. The objective of this proposal is to evaluate our new QPMC in comparison to the current punishment model. We propose to do this through two specific aims. In Aim 1, we will compare QPMC and the current punishment model in their ability to identify two biochemically distinct groups of rats self-administering sucrose pellets and METH (0.1 mg/kg/infusion). Given that the METH dose may alter the punishment sensitivity, Aim 2 will examine the effect of a changing METH dose on the reliability of the QPMC relative to the current punishment model. Animals from both aims will be evaluated for expression of corticotrophin releasing hormone stress systems, opioid peptide systems, and CART peptide systems in the nucleus accumbens. These molecular pathways will serve as molecular endpoints to establish biochemical distinctions between the identified groups per QPMC and the current model. Our general hypothesis is that, compared to the current punishment model, QPMC will objectively reveal distinct populations of rats self-administering METH under the punishment paradigm and will identify different endophenotypes for METH intake, leading to clearer understanding of the mechanisms that govern METH-UD.

项目摘要 甲基苯丙胺使用障碍（Meth-ud）的一个特征是，有些人会继续服用甲基苯丙胺 尽管负面的社会心理后果，而其他人则将在相同的条件下停止。理解 这些群体之间差异的机制将使新的发展 Meth-ud的药物治疗对于解决持续的健康危机至关重要。为此建模 现象，科学家开发了一种使用惩罚条件的临床前惩罚模型（例如， 增加脚垫强度，FSI）与甲基自动给药配对以区分冲击敏感（SS） 和防震（SR）大鼠。但是，尽管该领域被广泛接受，但 惩罚模型受到对主观和任意终点的依赖的限制，以区分SS和SR 小组的鲁棒性，可重复性和可靠性受到限制。解决固有的弱点 在当前的惩罚方案中，我们开发了一种新颖的定量和客观方法 带有聚类的定量惩罚模型（QPMC）。 QPMC从 在惩罚方案之前和之后采取行为，然后是客观地聚类 确定不同的群体。我们提供的初步数据表明QPMC优于电流 惩罚模式，以确定真正在生化上与众不同的人群。更广泛的采用 QPMC将需要在两个模型之间进行更广泛的比较。该提议的目的是 与当前的惩罚模型相比，评估我们的新QPMC。我们建议通过两个 具体目标。在AIM 1中，我们将比较QPMC和当前的惩罚模型，以识别两个 生化不同的大鼠群体自我管理的蔗糖颗粒和甲基（0.1 mg/kg/infusion）。给出 甲基剂量可能会改变惩罚的敏感性，AIM 2将检查甲基甲基苯丙胺变化的效果 QPMC相对于当前惩罚模型的可靠性。两个目标的动物将是 评估了释放激素应激系统，阿片类肽系统和 伏隔核中的CART肽系统。这些分子途径将用作分子 终点是每个QPMC和当前模型之间确定的组之间建立生化区别的终点。 我们的总体假设是，与当前的惩罚模型相比，QPMC将客观地揭示 在惩罚范式下自我管理的甲基甲基苯丙胺的不同人群，并将确定不同的 用于甲基甲基摄入量的内表型，从而更清楚地理解了控制甲基类的机制。