The Role of Orexin and Subthalamic Nucleus in Cocaine Demand

描述（由申请人提供）：吸毒成瘾仍然是一个主要的公共卫生问题。在某种程度上，这是因为吸毒者倾向于病态地对食物、人际关系、个人成就等自然奖励表现出低价值，同时不顾负面后果地寻求毒品。这种自然奖励和药物奖励之间的病理差异在大鼠中是可逆的，通过损伤双侧丘脑底核（STN）或通过对STN进行深部脑刺激（DBS），如治疗帕金森病所做的那样。虽然STN的DBS可能是药物滥用的一种前瞻性治疗方法，但其效果是非特异性的，副作用极大地限制了其应用。一种更可行的治疗方法是选择性地靶向介导STN损伤治疗效果的神经元通路。因此，这一建议概述了一系列的实验，将确定STN的作用，以及它的食欲能输入，在调解可卡因的动机。我们假设，抑制STN神经活动会降低自我使用可卡因的动机，但不会降低蔗糖的动机，也不会改变获取可卡因所需的努力较低时的可卡因摄入量。我们进一步假设，当获得可卡因所需的努力很高时，向STN输入的食欲能参与了可卡因的动机。这些基于初步数据的假设将通过两个具体目标进行检验。目的1将采用药理学方法来确定特异性和短暂性抑制STN内神经元对自我给药可卡因或蔗糖动机的影响，目的2将确定下丘脑对STN的食欲能输入在自我给药可卡因或蔗糖动机中的作用。在这两个目标中，自我给药的动机将通过行为经济学分析来评估，该分析测量了动物愿意花费在自我给药上的动机峰值以及其他一些次要措施。除了阐明STN和它的食欲能输入在自我使用可卡因的动机中的作用外，本研究

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.