Participation of Hypocretin in Compulsive-like Cocaine Taking and Relapse

描述(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毒品的模式，包括全神贯注于获得药物、反复寻找和服用药物以及对药物摄取失去控制(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的强迫性特征是过度的寻求和吸毒行为模式，包括药物摄入量的增加、进行性比率断点的增加、面对惩罚时的寻求毒品、戒毒期间大脑奖赏阈值的提高以及灭绝后恢复寻求可卡因(Wee等人，2007a；Ahmed等人，2002年)。强迫性类可卡因的服用，部分是通过大脑应激系统的神经适应发生的，该系统调节维持依赖药物状态所需的激励过程中涉及的负面情绪状态(参见Koob，2008)。此外，文献中有很好的文献记载，应激系统在灭绝后寻求毒品的恢复中发挥重要作用，这是药物复发的一个模式(供综述，Shaham等人，2003；Lu等人，2003)。最近，下丘脑外侧下丘脑-食欲素(HCRT)系统被认为与吸毒和恢复药物寻找有关(综述见Boutrel等人，2010年)。有趣的是，有限的 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延伸杏仁核的CRF来推动药物寻找(Boutrel等人，2005年；Hata等人，2011年)。HCRT在与可卡因成瘾相关的强迫行为的出现和持续中所起的作用尚未完全阐明。因此，当前研究建议的目标是描述HCRT在调节递增比率断点、对毒品的惩罚抵抗反应和在灭绝后恢复寻求毒品方面的作用。为了实现这一目标，我们将使用成瘾的扩展获得模型和HCRT-1受体拮抗剂和/或病毒载体介导的HCRT基因敲除来确定HCRT在动物强迫寻求药物行为中的作用程度，以及应激和线索诱导的可卡因灭绝后寻求可卡因的恢复。最后，Western印迹分析将被用来确定HCRT在可卡因摄入增加后腹侧被盖区和扩大的杏仁核内的生化神经适应中的作用。

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.