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首页> 外文学位 >Llevo-tetrahydropalmatine (l-THP) and low dose naltrexone (LDN): A Novel Combination for the Prevention of Cocaine Relapse.
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Llevo-tetrahydropalmatine (l-THP) and low dose naltrexone (LDN): A Novel Combination for the Prevention of Cocaine Relapse.

机译：左旋四氢巴马汀（l-THP）和低剂量纳曲酮（LDN）：预防可卡因复发的新型药物。

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摘要

To date, FDA is yet to approve a medication for the treatment of cocaine dependence or for the prevention of cocaine relapse. One promising potential treatment is l-THP, primarily a modest dopamine antagonist. However, l-THP possesses unwanted sedative side effects, which could be difficult to overcome clinically. The present study aims to develop an improved cocaine relapse treatment, creating an l-THP based combination medication. Our preliminary experiments determined l-THP when co-administered with LDN, decreased the sedative effect and increased the efficacy of l-THP. As a result, the focus of this dissertation was placed on the development of l-THP & LDN as a combination medication for the prevention of cocaine relapse. Specific aims used to accomplish the objective were: 1) determine the efficacy of l-THP & LDN combination for attenuation of cocaine seeking behavior as well as minimization of sedative effect of l-THP and 2) investigate the mechanism of l-THP & LDN through beta-endorphin release and POMC expression. The combination of l-THP & LDN attenuated reinstatement of conditioned place preference as well as drug-seeking behavior in the reinstatement of cocaine self-administration. Additionally, the l-THP sedative effect observed at the 3mg/kg and 5mg/kg l-THP doses was ameliorated through co-administration of 0.1mg/kg LDN. Taken together, results of the behavioral studies indicate 3mg/kg l-THP & 0.1mg/kg LDN has the greatest potential as a cocaine relapse prevention treatment. This dosage was used to examine the effect of l-THP & LDN on endogenous beta-endorphin release and POMC expression. In animals treated with 3mg/kg l-THP & 0.1mg/kg LDN, we correlated the reduction of drug seeking with an increase of plasma beta-endorphin and hypothalamic POMC mRNA expression. This to our knowledge is the first study investigating the underlying mechanism of LDN. The research presented in this dissertation establishes l-THP & LDN as novel treatment for the prevention of cocaine relapse and dependence with great potential for future clinical translation.
机译：迄今为止，FDA尚未批准用于治疗可卡因依赖或预防可卡因复发的药物。一种有前途的潜在治疗方法是l-THP，主要是一种适度的多巴胺拮抗剂。然而，1-THP具有不良的镇静副作用，这在临床上可能难以克服。本研究旨在开发一种改进的可卡因复发治疗，创造一种基于l-THP的联合药物。我们的初步实验确定了L-THP与LDN并用时的镇静作用，并提高了L-THP的疗效。因此，本论文的重点放在了预防可卡因复发的联合用药L-THP和LDN的开发上。用于实现该目标的具体目的是：1）确定l-THP和LDN组合对可卡因寻求行为的缓解作用以及l-THP的镇静作用最小化的效果； 2）研究l-THP和LDN的作用机理通过β-内啡肽释放和POMC表达。 l-THP和LDN的组合减弱了可卡因自我给药的恢复中条件性位置偏好的恢复和药物寻找行为。另外，通过共同施用0.1mg / kg LDN，改善了在3mg / kg和5mg / kg l-THP剂量下观察到的l-THP镇静作用。总体而言，行为研究的结果表明3mg / kg的L-THP和0.1mg / kg的LDN具有最大的潜力可卡因预防复发。该剂量用于检查1-THP和LDN对内源性β-内啡肽释放和POMC表达的影响。在用3mg / kg l-THP和0.1mg / kg LDN治疗的动物中，我们将寻找药物的减少与血浆β-内啡肽和下丘脑POMC mRNA表达的增加联系起来。据我们所知，这是第一个研究LDN潜在机制的研究。本文提出的研究将l-THP和LDN确立为预防可卡因复发和依赖性的新方法，具有很大的临床应用前景。

著录项

  • 作者

    Sushchyk, Sarah Ashley.;

  • 作者单位

    University of Maryland, Baltimore.;

  • 授予单位 University of Maryland, Baltimore.;
  • 学科 Pharmaceutical sciences.
  • 学位 Ph.D.
  • 年度 2015
  • 页码 134 p.
  • 总页数 134
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 地球物理学;
  • 关键词

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