Viral-Mediated GDNF Expression and Cocaine Addiction

病毒介导的 GDNF 表达和可卡因成瘾

• 批准号: 7393359
• 负责人: Robert Nelson Pechnick
• 金额: $ 24.38万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7393359
• 关键词: Adenovirus Vector; Adult; Affect; Area; Behavior; Brain; Brain Diseases; Cessation of life; Cocaine; Cocaine Dependence; Collaborations; Data; Development; Drug abuse; Food; Foundations; Gene Transduction Agent; Gene Transfer; Genes; Goals; Intervention; Mediating; Medical; Motor Activity; Neuraxis; Nucleus Accumbens; Pharmaceutical Preparations; Property; Rattus; Research Personnel; Research Project Grants; Rewards; Self Administration; Site; Specificity; System; Testing; Tissues; Treatment Efficacy; United States; Viral; concept; design; drug of abuse; experience; gene therapy; glial cell-line derived neurotrophic factor; neurotransmission; neurotrophic factor; reinforced behavior; research study; response; vector

DESCRIPTION (provided by applicant): Cocaine produces many medical and psychiatric complications, and its use is the major cause of drug-related deaths in the United States. Although a tremendous amount of effort has been spent on pharmacologic and other interventions, few treatment options exist for cocaine dependence. Neurotrophic factors have been implicated in activity-dependent plasticity in the adult central nervous system, including the adaptational responses to drugs of abuse. Provocative data have been generated showing the involvement of glial cell line- derived neurotrophic factor (GDNF) in these adaptive responses. GDNF has pronounced effects on central dopaminergic systems, and cocaine addiction is associated with decreases in brain levels of GDNF. One approach to increase GDNF levels at specific brain target sites in a sustained manner is by the use of gene therapy. Current gene therapy vectors allow the long-term expression of GDNF at selected target sites. The overall goal of this application for an Exploratory/Developmental Research Grant (R21) is to express GDNF genes in rat brain using an inducible adenovirus vector, and to determine its therapeutic efficacy in treating cocaine addiction. The first specific aim will test the hypothesis that increasing the expression of GDNF in the nucleus accumbens will reduce the reinforcing effects of cocaine. We will determine if the effects of GDNF hyper-expression on cocaine self-administration are long-lasting, and ascertain the specificity by evaluating whether the motoric effects of cocaine and food-reinforced behavior also are affected. The second specific aim will characterize the effects of viral-mediated GDNF expression on markers of dopaminergic neurotransmission in order to begin to elucidate the mechanisms by which GDNF decreases the reinforcing properties of cocaine. The results of the proposed experiments will establish proof of concept and feasibility and will build the foundation that will allow us to design and carry-out more comprehensive studies characterizing the effects of vector-delivered GDNF on drug self-administration.

描述（由申请人提供）：可卡因会产生许多医学和精神病并发症，其使用是美国与药物有关的死亡的主要原因。尽管在药理学和其他干预措施上已经花费了巨大的努力，但可卡因依赖性几乎没有治疗选择。神经营养因素与成人中枢神经系统的活性依赖性可塑性有关，包括对滥用药物的适应性反应。已经生成了挑衅性数据，显示了神经胶质细胞系的神经营养因子（GDNF）参与这些自适应反应。 GDNF对中央多巴胺能系统具有明显的影响，可卡因成瘾与GDNF大脑水平降低有关。通过使用基因治疗，一种以持续的方式增加了特定大脑靶位点的GDNF水平的方法。当前的基因治疗载体允许在选定的靶位点上长期表达GDNF。该应用探索性/发育研究补助金（R21）的总体目标是使用诱导的腺病毒载体在大鼠大脑中表达GDNF基因，并确定其在治疗可卡因成瘾中的治疗功效。第一个具体目的将检验以下假设：伏隔核中GDNF的表达增加将减少可卡因的增强作用。我们将确定GDNF高表达对可卡因自我给药的影响是否长期持久，并通过评估可卡因和食物增强行为的摩擦效应来确定特异性。第二个特定目的将表征病毒介导的GDNF表达对多巴胺能神经传递标记的影响，以便开始阐明GDNF降低可卡因的增强特性的机制。拟议的实验的结果将建立概念和可行性证明，并将建立基础，使我们能够设计和进行更全面的研究，以表征载体传递的GDNF对药物自我管理的影响。