The Role of Orexin and Subthalamic Nucleus in Cocaine Demand

描述(申请人提供)：吸毒成瘾仍然是一个主要的公共卫生问题。这在一定程度上是因为吸毒者往往在自然回报方面表现出病态的低价值，例如食物、人际关系、个人成就，同时不顾负面后果寻求毒品。这种自然奖赏和药物奖赏之间的病理差异在大鼠身上是可逆的，可以通过损毁双侧丘脑底核(STN)或通过STN的脑深部刺激(DBS)来逆转，就像治疗帕金森氏症一样。尽管STN的DBS可能是一种有前景的药物滥用治疗方法，但其疗效非特异性，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针对介导STN损伤治疗效果的神经通路。因此，这项建议概述了一系列实验，以确定STN及其食欲素能输入在调节可卡因动机中的作用。我们假设，当获得可卡因的努力很高时，抑制STN神经活动将降低自我给予可卡因的动机，而不会减少获得蔗糖的动机，或者在获得可卡因的努力较低时改变可卡因的摄入量。我们进一步假设，当获得可卡因所需的努力很高时，对STN的食欲素能输入与可卡因的动机有关。这些假设基于初步数据，将通过两个具体目标进行检验。目标1将采用药物遗传学方法来确定特异性和瞬时抑制STN内的神经元对自我给予可卡因或蔗糖的动机的影响，而目标2将确定下丘脑Orexine能传入STN在自我给予可卡因或蔗糖的动机中的作用。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，该分析衡量了动物愿意花费在自我给药上的峰值动机，以及其他几种次要措施。除了阐明STN及其食欲素能输入在自我注射可卡因的动机中的作用外，这篇文章还 奖学金将对申请人进行最尖端的技术培训，以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.