Viral-Mediated GDNF Expression and Cocaine Addiction

说明（由申请人提供）：可卡因会产生许多医疗和精神并发症，在美国，使用可卡因是与毒品有关的死亡的主要原因。尽管在药理学和其他干预措施上付出了巨大的努力，但对可卡因依赖的治疗选择很少。神经营养因子与成人中枢神经系统的活动依赖性可塑性有关，包括对滥用药物的适应性反应。已产生的令人振奋的数据显示，胶质细胞系来源的神经营养因子（GDNF）参与这些适应性反应。GDNF对中枢多巴胺能系统有明显的影响，可卡因成瘾与大脑GDNF水平的降低有关。以持续的方式增加特定脑靶部位GDNF水平的一种方法是使用基因治疗。目前的基因治疗载体允许GDNF在选定的目标部位长期表达。本次申请探索性/发展性研究基金（R21）的总体目标是利用诱导性腺病毒载体在大鼠脑中表达GDNF基因，并确定其治疗可卡因成瘾的疗效。第一个具体的目标是测试一个假设，即增加伏隔核中GDNF的表达将减少可卡因的强化作用。我们将确定GDNF高表达对可卡因自我给药的影响是否持久，并通过评估可卡因和食物强化行为的运动效应是否也受到影响来确定其特异性。第二个具体目标将描述病毒介导的GDNF表达对多巴胺能神经传递标志物的影响，以便开始阐明GDNF降低可卡因强化特性的机制。拟议实验的结果将建立概念和可行性的证明，并将建立基础，使我们能够设计和开展更全面的研究，表征载体传递的GDNF对药物自我给药的影响。

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.