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.

项目概要 甲基苯丙胺使用障碍 (METH-UD) 的特征之一是有些人会继续服用甲基苯丙胺 尽管会产生负面的心理社会后果，但其他人会在相同条件下停止。理解 管理这些群体之间差异的机制将有助于开发新的 METH-UD 的药物疗法对于解决持续的健康危机非常重要。为了模拟这个 为了解决这一现象，科学家们开发了一种使用惩罚条件的临床前惩罚模型（例如， 增加足部电击强度 (FSI) 与自我注射冰毒 (METH) 相结合，以区分电击敏感 (SS) 和抗休克（SR）大鼠。然而，尽管该领域被广泛接受，但当前版本 惩罚模型因其依赖主观和任意终点来区分 SS 和 SR 而受到限制 组，因此其稳健性、再现性和可靠性受到限制。解决固有的弱点 在当前的惩罚协议中，我们开发了一种新颖的定量和客观方法，我们将其命名为 聚类定量惩罚模型（QPMC）。 QPMC 从以下位置获取多个变量： METH 采集惩罚方案前后的行为，然后进行聚类以客观 确定不同的组。我们提供的初步数据表明 QPMC 优于当前的 关于识别真正具有生化特征的群体的惩罚模型。更广泛采用 QPMC 需要对这两个模型进行更广泛的比较。该提案的目的是 与当前的惩罚模型相比，评估我们的新 QPMC。我们建议通过两个途径来做到这一点 具体目标。在目标 1 中，我们将比较 QPMC 和当前的惩罚模型识别两个 生化上不同的大鼠组自行施用蔗糖丸和冰毒（0.1 mg/kg/输注）。给定 METH 剂量可能会改变惩罚敏感性，目标 2 将检查改变 METH 的效果 相对于当前惩罚模型，QPMC 的可靠性受到了一定程度的影响。来自两个目标的动物将 评估促肾上腺皮质激素释放激素应激系统、阿片肽系统和 伏隔核中的 CART 肽系统。这些分子途径将作为分子 终点以确定每个 QPMC 和当前模型确定的组之间的生化差异。 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 不同的老鼠群体在惩罚范式下自我施用冰毒，并会识别出不同的 METH 摄入的内表型，使人们更清楚地了解 METH-UD 的控制机制。