Neurochemical mechanisms governing footshock-induced suppression of methamphetamine intake

项目摘要 甲基苯丙胺使用障碍的一个特点是，有些人会继续服用甲基苯丙胺。 尽管有负面的心理社会后果，而其他人在同样的条件下会停止。理解 管理这些群体之间差异的机制将使新的 这将有助于开发METH-UD的药物疗法，并将对解决当前的健康危机至关重要。来模拟这个 现象，科学家们开发了一种临床前惩罚模型，该模型使用惩罚条件（例如， 增加足电击强度，FSI）与METH自我给药配对，以区分休克敏感性（SS） 和抗休克（SR）大鼠。然而，尽管在该领域中被广泛接受， 惩罚模型的局限性在于它依赖于主观和任意的端点来区分SS和SR 组，因此在其鲁棒性、再现性和可靠性方面受到限制。为了解决固有的弱点， 在当前的惩罚协议中，我们开发了一种新的定量和客观的方法，我们将其命名为 聚类定量惩罚模型（QPMC）QPMC从 方法采取行为前、后惩罚方案，其次进行聚类，以客观 确定不同的群体。我们目前的初步数据表明，QPMC是上级的电流 惩罚模型来识别真正具有生物化学特征的种群。更广泛地采用 QPMC将需要对两种模型进行更广泛的比较。这项建议的目的是 与当前的惩罚模式相比，评估我们新的QPMC。我们建议通过两个 具体目标。在目标1中，我们将比较QPMC和当前惩罚模型识别两个 生物化学上不同的大鼠组自我施用蔗糖丸和METH（0.1mg/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 QPMC相对于当前惩罚模型的可靠性。两个目标的动物将是 评价促肾上腺皮质激素释放激素应激系统、阿片肽系统的表达， CART肽系统在神经核中。这些分子途径将作为分子 终点，以确定根据QPMC和当前模型确定的组之间的生化差异。 我们的一般假设是，与目前的惩罚模式相比，QPMC将客观地揭示 不同的大鼠群体在惩罚范式下自我管理METH，并将识别不同的 METH摄入量的内在表型，从而更清楚地了解管理METH-UD的机制。

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.