The Role of Orexin and Subthalamic Nucleus in Cocaine Demand

描述（由申请人提供）：药物成瘾仍然是一个主要的公共卫生问题。这部分是因为药物滥用者往往对自然奖励表现出病态的低价值，例如食物，关系，个人成就，同时寻求药物而不考虑负面后果。自然奖励和药物奖励之间的这种病理学差异在大鼠中是可逆的，通过双侧丘脑底核（subthalamic nucleus，DBS）损伤或通过脑深部电刺激（deep brain stimulation，DBS）在丘脑底核（subthalamic nucleus，DBS）中进行，如用于治疗帕金森病。虽然DBS的药物滥用可能是一个前瞻性的治疗药物滥用，其影响是非特异性的副作用，大大限制了其应用。更可行的疗法将是选择性靶向介导损伤治疗效果的神经元通路的疗法。因此，该提案概述了一系列实验，将确定的作用，其orexinergic输入，在调解可卡因的动机。我们假设，当获得可卡因所需的努力很高时，抑制神经元活动将降低自我管理可卡因的动机，而不会降低蔗糖的动机或改变可卡因的摄入量，当获得可卡因所需的努力很低时。我们进一步假设，orexinergic输入到cardiac参与可卡因的动机时，需要努力获得可卡因是高的。这些假设基于初步数据，将通过两个具体目标进行检验。目的1将采用药物遗传学方法来确定特异性和瞬时抑制内的神经元对自我管理可卡因或蔗糖的动机的影响，目的2将确定下丘脑食欲素能输入的作用，以自我管理可卡因或蔗糖。在这两个目的中，将通过行为经济学分析评估自我给药的动机，该分析测量动物愿意花费以自我给药的峰值动机以及其他几个次要指标。除了阐明可卡因及其食欲素能输入在自我施用可卡因动机中的作用外， 奖学金将培训申请人在最前沿的技术，用于分析已识别的神经回路的行为功能。

DESCRIPTION (provided by applicant): Drug addiction remains a major public health issue. This is, in part, because drug abusers tend to display a pathologically low value for natural rewards, e.g. food, relationships, personal achievement, while simultaneously seeking drug regardless of the negative consequences. This pathological disparity between natural rewards and drug rewards is reversible in rats by lesioning subthalamic nucleus (STN) bilaterally or by deep brain stimulation (DBS) in STN, as is done for treatment of Parkinson's disease. Although DBS of STN may be a prospective treatment for drug abuse, its effects are nonspecific with side effects that dramatically limit its application. A more viable therapy would be one that selectivel targets the neuronal pathways that mediate the therapeutic effects of STN lesioning. Hence, this proposal outlines a series of experiments that will determine the role of STN, and its orexinergic inputs, in mediating motivation for cocaine. We hypothesize that inhibiting STN neural activity will decrease motivation to self-administer cocaine when effort required to obtain cocaine is high without decreasing motivation for sucrose or altering cocaine intake when effort required to obtain cocaine is low. We further hypothesize that orexinergic input to STN is involved in motivation for cocaine when effort required to obtain cocaine is high. These hypotheses, based upon preliminary data, will be tested through two specific aims. Aim 1 will employ a pharmacogenetic approach to determine the effects of specifically and transiently inhibiting the neurons within STN on motivation to self-administer cocaine or sucrose, and Aim 2 will determine the role of the hypothalamic orexinergic inputs to STN in the motivation to self-administer cocaine or sucrose. In both aims motivation to self-administer drug will be assessed via a behavioral-economic analysis that measures peak motivation an animal is willing to expend to self-administer drug as well as several other secondary measures. In addition to clarifying the role of STN and its orexinergic input in motivation to self-administer cocaine, this fellowship will train the applicant in the most cutting-edge techniques for analyzing behavioral functions of identified neural circuits.