Hypocretin contributions to compulsive methamphetamine self-administration in rats

下丘脑分泌素对大鼠强迫性甲基苯丙胺自我给药的贡献

• 批准号: 10218129
• 负责人: Brooke E Schmeichel
• 金额: $ 24.9万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218129
• 关键词: Abstinence; Acute; Affect; Amygdaloid structure; Animal Model; Animals; Arousal; Attenuated; Axon; Behavior; Behavioral; Brain; Cell Count; Chemosensitization; Chronic; Clinical Research; Compulsive Behavior; Data; Dependence; Disease; Dorsal; Drug Addiction; Drug Use Disorder; Drug abuse; Drug usage; Emotional; Ethanol; Functional disorder; Goals; Heroin; Human; Hypothalamic structure; Individual; Intake; Intravenous; Lateral; Measures; Medial; Mediating; Methamphetamine; Methamphetamine dependence; Modeling; Motivation; Negative Reinforcements; Neurons; Neuropeptides; Nicotine; Nucleus Accumbens; Pattern; Pharmaceutical Preparations; Pharmacology; Play; Presynaptic Terminals; Property; Publishing; Punishment; Rattus; Recovery; Regulation; Reinforcement Schedule; Relapse; Research Proposals; Resistance; Rewards; Rodent; Role; Self Administration; Signal Transduction; Site; Sleep; Sleep Disorders; Sleep disturbances; Stress; Structure; Structure of terminal stria nuclei of preoptic region; Substance abuse problem; Symptoms; System; Testing; Therapeutic; Time; Ventral Tegmental Area; Withdrawal; Work; addiction; attenuation; basal forebrain; circadian; cocaine self-administration; dependence relapse; drug abstinence; genetic manipulation; hypocretin; insight; methamphetamine abuse; motivational processes; negative emotional state; neural circuit; neuroadaptation; neurotransmission; non rapid eye movement; orexin A receptor; preclinical efficacy; preclinical study; psychostimulant; receptor; recruit

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.

项目总结/摘要 精神兴奋剂，包括甲基苯丙胺（METH），是一种广泛滥用的药物， 加强和提高唤醒效果，促进其使用和滥用。冰毒成瘾是一种 人类和动物最终都从非依赖性的间歇性药物使用过渡到强迫性药物 拿。啮齿类药物成瘾模型中的毒性特征在于药物过量模式 寻求/服用行为，包括药物摄入量的增加，获得药物的动机增加（即， 累进比率断点升高，面对惩罚时吸毒）， 戒断药物，并增加复发的可能性（Ahmed等，2002; Wee等人，2007年; Mantsch 例如，2008年）。强迫性吸食冰毒，部分是通过大脑应激系统的神经适应发生的， 特别是在延伸的杏仁核中，它介导与动机有关的负面情绪状态。 维持药物依赖状态所需的过程（有关审查，见Koob，2008年）。横向 下丘脑与奖赏、压力和唤醒系统有关，主要是通过下丘脑泌素/食欲素 （HCRT）投射神经元仅位于背侧下丘脑内（为了综述，Boutrel等人，二○一○年; Marchant等人，2012年）。HCRT神经传递一直被证明在尼古丁中起作用， 乙醇和海洛因自我给药行为。然而，HCRT大脑的直接贡献 压力系统与METH自我管理相关的强迫行为的出现仍然是 被阐明。除了在成瘾中的作用外，HCRT还被认为在调节 唤醒（综述，de Lecea等人，2012年）。有趣的是，许多临床研究表明， 睡眠功能障碍与药物滥用和/或复发之间的关系（Brower等人，2001; Pace-Schott等人，二○ ○五年; Teplin等人，2006年）。尽管有这些观察结果，但很少进行临床前研究， 药物滥用中昼夜节律系统破坏的直接或因果作用，代表了 我们的理解。此外，目前还没有发表的研究集中在HCRT的贡献 神经传递到强迫性的METH服用/寻找。因此，本研究提案的目标是 描述HCRT在导致状态依赖和唤醒的负强化中的作用- 强迫性吸食冰毒的相关动机为了实现这一目标，我们将结合使用 光和化学遗传学操作，以及无线电遥测睡眠/觉醒数据，以确定 HCRT参与强制性METH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 神经传递有助于大鼠强迫性METH服用的状态依赖性动机方面。在 此外，我们将描述药物依赖期间强迫性METH服用的唤醒状态功能障碍， 禁欲和复发