Viral-Mediated GDNF Expression and Cocaine Addiction

描述（由申请人提供）：可卡因产生许多医疗和精神并发症，其使用是美国药物相关死亡的主要原因。虽然在药物和其他干预措施方面已经付出了巨大的努力，但可卡因依赖性的治疗选择很少。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。已经产生了挑衅性的数据，显示胶质细胞系衍生的神经营养因子（GDNF）参与这些适应性反应。GDNF对中枢多巴胺能系统有明显的作用，可卡因成瘾与脑GDNF水平的降低有关。一种以持续的方式增加特定脑靶位点的GDNF水平的方法是使用基因治疗。目前的基因治疗载体允许GDNF在选定的靶位点长期表达。本申请的探索性/发展性研究资助（R21）的总体目标是使用诱导型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。第一个具体的目标将测试这一假设，即增加GDNF在丘脑核中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是持久的，并通过评估可卡因的运动效应和食物强化行为是否也受到影响来确定特异性。第二个具体的目标将表征病毒介导的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降低可卡因的增强特性的机制。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，使我们能够设计和进行更全面的研究，表征载体递送GDNF对药物自我管理的影响。

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.