Hypocretin contributions to compulsive methamphetamine self-administration in rats

项目摘要/摘要 精神刺激剂，包括甲基苯丙胺，是一类被广泛滥用的药物，具有很强的药效。 增强和唤醒效果，助长了它们的使用和滥用。冰毒成瘾是一种精神障碍 人类和动物最终都会从非依赖的间歇性药物使用过渡到强迫性药物 夺取。啮齿动物药物成瘾模型的强迫性以过量药物模式为特征 寻求/服用行为，包括药物摄入量的增加，增加了获得药物的动机(即 累进比断点升高，面对惩罚吸毒)，奖励制度缺陷 戒毒和复发的可能性增加(Ahmed等人，2002；Wee等人，2007；Mantsch 等人，2008年)。强迫性服用冰毒，部分是通过大脑压力系统的神经适应来发生的， 特别是在延伸的杏仁核中，它调节与动机有关的负面情绪状态 维持依赖药物状态所需的程序(审查，见Koob，2008)。侧向 下丘脑与奖赏、压力和唤醒系统有关，主要是通过下丘脑/食欲素。 (HCRT)仅位于下丘脑背侧的投射神经元(供回顾，Boutrel等人，2010； Marchant等人，2012年)。HCRT神经传递一直被证明在尼古丁中发挥作用， 乙醇和海洛因在大鼠体内的自我给药行为。然而，HCRT脑的直接贡献 应激系统对强迫症行为的出现与冰毒自我管理的关系尚待解决 将被澄清。除了在成瘾中起作用外，hcrt被认为在调节 觉醒(供审查，De Lecea等人，2012年)。有趣的是，一些临床研究表明 睡眠障碍与药物滥用和/或复发之间的关系(Brower等人，2001年；Pace-Schott等人，2005年； Teplin等人，2006年)。尽管有这些观察，但很少有临床前研究调查 在物质滥用中昼夜节律系统紊乱的直接或原因作用，代表着在 我们的理解是。此外，目前还没有发表的研究集中于HCRT的贡献 强迫症样冰毒服用/寻求的神经传递。因此，当前研究提案的目标是 为了表征HCRT在促进状态依赖和觉醒的负性强化中的作用- 强迫性吸食冰毒的相关激励因素。为了实现这一目标，我们将结合使用 光学和化学遗传学操作，结合无线电遥测睡眠/唤醒数据，以确定 HCRT参与强迫性冰毒服用的程度。我们将使用扩展访问模型 成瘾和神经回路的遗传操作以确定HCRT的程度 神经传递有助于大鼠服用强迫性冰毒的状态依赖的动机方面。在……里面 此外，我们还将描述在药物依赖期间强制服用冰毒的唤醒状态障碍， 禁欲和故态复萌。

Project Summary/Abstract Psychostimulants, including methamphetamine (METH), are a widely abused class of drugs that exert robust reinforcing and arousal-enhancing effects, contributing to their use and abuse. METH addiction is a disorder in which both humans and animals ultimately transition from nondependent episodic drug use to compulsive drug taking. Compulsivity in rodent drug addiction models is characterized by excessive patterns of drug seeking/taking behavior, including escalation of drug intake, increased motivation to obtain the drug (i.e. elevated progressive ratio breakpoints, drug taking in the face of punishment), reward system deficits during abstinence from the drug, and increased likelihood of relapse (Ahmed et al., 2002; Wee et al., 2007; Mantsch et al., 2008). Compulsive METH taking, in part, occurs through neuroadaptations of brain stress systems, particularly within the extended amygdala, that mediate negative emotional states implicated in motivational processes required for maintaining the dependent drug state (for review, see Koob, 2008). The lateral hypothalamus has been implicated in reward, stress and arousal systems, largely via hypocretin/orexin (HCRT) projection neurons located solely within the dorsal hypothalamus (for review, Boutrel et al., 2010; Marchant et al., 2012). HCRT neurotransmission has consistently been shown to play a role in nicotine, ethanol, and heroin self-administration behavior in rats. However, the direct contribution of the HCRT brain stress system to the emergence of compulsive behaviors associated with METH self-administration remains to be elucidated. In addition to a role in addiction, HCRT is posited to play a significant role in the regulation of arousal (for review, de Lecea et al., 2012). Interestingly, a number of clinical studies indicate associations between sleep dysfunction and drug abuse and/or relapse (Brower et al., 2001; Pace-Schott et al., 2005; Teplin et al., 2006). Despite these observations, few preclinical studies have been conducted investigating the direct or causative role for circadian system disruption in substance abuse, representing a significant lacuna in our understanding. Furthermore, there are currently no published studies focused on the contribution of HCRT neurotransmission to compulsive-like METH taking/seeking. Thus, the goal of the current research proposal is to characterize the role of HCRT in the negative reinforcement that contributes to state-dependent and arousal- related motivational aspects of compulsive METH taking. To achieve this goal, we will use a combination of opto-and chemo-genetics manipulations, together with radiotelemetry sleep/wake data, to determine the degree to which HCRT participates in compulsive METH taking. We will use an extended access model of addiction and genetic manipulations of neurocircuitry to determine the degree to which HCRT neurotransmission contributes to state-dependent motivational aspects of compulsive METH taking in rats. In addition, we will characterize arousal state dysfunction of compulsive METH taking during drug dependence, abstinence, and relapse.