Participation of Hypocretin in Compulsive-like Cocaine Taking and Relapse

描述（由申请人提供）：可卡因滥用每年影响全国约170万人，其特征是过度寻求和服用药物的模式，包括专注于获得药物、重复寻求和服用药物以及对药物摄入失去控制（美国精神病学协会，2000年）。实验动物在长期接触可卡因自我给药时表现出类似的强迫行为。啮齿动物药物成瘾模型中的nasivity的特征在于药物寻求和服用行为的过度模式，包括药物摄入的升级、升高的渐进比率断点、面对惩罚的药物寻求、在药物戒断期间脑奖励阈值的升高以及在消失后可卡因寻求的恢复（Wee等人，2007 a; Ahmed等人，2002年）。强迫性的可卡因服用，部分是通过大脑应激系统的神经适应发生的，这些应激系统介导了与维持药物依赖状态所需的动机过程有关的负面情绪状态（有关综述，参见Koob，2008）。此外，在文献中有充分记载的是，应激系统在消退后的药物寻求恢复中起重要作用，这是药物复发的模型（综述，Shaham et al，2003; Lu et al，2003）。最近，外侧下丘脑下视丘分泌素/食欲素（HCRT）系统已经涉及药物服用和药物寻求的恢复（综述参见Boutrel等人; 2010）。有趣的是， 有证据表明HCRT可能通过激活与应激系统功能障碍有关的特定脑区，包括中皮质边缘系统的多巴胺能区和扩展杏仁核中的CRF，来驱动药物寻找（Boutrel等2005; Hata等，2011年）。HCRT在与可卡因成瘾相关的强迫行为的出现和持续中的作用尚未完全阐明。因此，目前的研究计划的目标是表征HCRT在介导增加的进展率断点，对药物的惩罚抵抗反应和灭绝后寻求药物的恢复中的作用。为了实现这一目标，我们将使用成瘾和HCRT-1受体拮抗剂和/或病毒载体介导的HCRT敲低的扩展访问模型，以确定HCRT在升级动物的强迫性药物寻求行为中发挥作用的程度，以及在灭绝后可卡因寻求的压力和线索诱导的恢复。最后，蛋白质印迹分析将被用来确定HCRT的作用，在腹侧被盖区和扩展杏仁核内的生化神经适应可卡因摄入量增加。

DESCRIPTION (provided by applicant): Cocaine abuse affects approximately 1.7 million individuals nationwide per year and is characterized by patterns of excessive drug seeking and taking, including a preoccupation with obtaining the drug, repetitive seeking and taking of the drug, and a loss of control over drug intake (American Psychiatric Association, 2000). Experimental animals exhibit similar compulsive behaviors when exposed to extended access to cocaine self- administration. Compulsivity in rodent drug addiction models is characterized by excessive patterns of drug seeking and taking behavior, including escalation of drug intake, elevated progressive ratio breakpoints, drug seeking in the face of punishment, elevation in brain reward thresholds during abstinence from the drug, and the reinstatement of cocaine seeking following extinction (Wee et al., 2007a; Ahmed et al., 2002). Compulsive- like cocaine taking, in part, occurs through neuroadaptations of brain stress systems that mediate negative emotional states implicated in motivational processes required for maintaining the dependent drug state (for review, see Koob, 2008). In addition, it is well documented within the literature that stress systems play a significant role in the reinstatement of drug seeking following extinction, a model of drug relapse (for reviews, Shaham et al, 2003; Lu et al, 2003). Recently, the lateral hypothalamic hypocretin/orexin (HCRT) system has been implicated in drug taking and the reinstatement of drug seeking (for review, see Boutrel et al; 2010). Interestingly, limited evidence suggests HCRT may be driving drug seeking through activation of specific brain regions implicated in stress system dysfunction, including dopaminergic regions of the mesocorticolimbic system and CRF in the extended amygdala (Boutrel et al 2005; Hata et al., 2011). The role of HCRT in the emergence and persistence of compulsive behaviors associated with cocaine addiction has yet to be fully elucidated. Thus, the goal of the current research proposal is to characterize the role of HCRT in the mediation of increased progressive ratio breakpoints, punishment-resistant responding for drug and reinstatement of drug seeking following extinction. To achieve this goal, we will use an extended access model of addiction and HCRT-1 receptor antagonist and/or viral-vector mediated HCRT knockdown to determine the degree to which HCRT plays a role in compulsive drug seeking behavior in escalated animals and stress- and cue-induced reinstatement of cocaine seeking following extinction. Finally, Western blot analyses will be used to determine the role of HCRT in the biochemical neuroadapations within the ventral tegmental area and extended amygdala following escalated cocaine intake.