Hypocretin Antagonists as a Novel Approach to Medication Development

下丘脑分泌素拮抗剂作为药物开发的新方法

• 批准号: 8233458
• 负责人: Richard W Foltin
• 金额: $ 38.86万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8233458
• 关键词: Acute; Agonist; Amphetamines; Appetitive Behavior; Arousal; Attenuated; Banana; Behavior; Brain; Candy; Clinical; Cocaine; Cocaine Dependence; Complex; Cues; Data; Development; Dose; Drops; Drug abuse; Eating; Eating Disorders; Food; Food deprivation (experimental); Glucose; Goals; Hydrocortisone; Hypothalamic structure; Incentives; Infusion procedures; Insulin; Lateral; Learning; Macaca mulatta; Measures; Mediating; Memory; Modeling; Monkeys; Neurons; Neuropeptides; Papio; Pharmaceutical Preparations; Play; Procedures; Psychological reinforcement; Relapse; Rodent; Role; Self Administration; Self-Administered; Stress; System; Techniques; base; deprivation; disorder later incidence prevention; drug relapse; food consumption; food flavor; hypocretin; improved; nonhuman primate; novel; novel strategies; novel therapeutic intervention; orexin A; orexin B; paired stimuli; preference; public health relevance; reinforced behavior; reinforcer; response; stressor

DESCRIPTION (provided by applicant): The neuropeptides hypocretin-1 and -2 (de Lecea et al., 1998) also known as orexin-A and -B (Sakurai et al., 1998) derive from the lateral hypothalamus and project throughout the brain. Hypocretin plays a role in modulating arousal, foraging for food in rodents, the response to stress, and learning and memory. Hypocretins also play a role in drug-reinforced behavior by modulating 1) the salience of stimuli paired with drug, as assessed using condition-place preference models, 2) the magnitude of response to drug following repeated dosing, i.e., sensitization, and 3) the ability of environmental cues and stress to elicit reinstatement in relapse models. These data suggest that hypocretin-mediated arousal has motivating effects and increases the salience of cues associated with reinforcement. Given the societal problems of eating disorders and cocaine- dependence, a carefully controlled assessment of the influence of hypocretin agonists and antagonists on cocaine- and food-seeking and self-administration in non-human primates is highly significant. Aim 1a: Determine the effects of a hypocretin-1 antagonist, and agonist and agonist/antagonist combinations on the appetitive and consummatory aspects of responding for banana-flavored food pellets by 6 rhesus monkeys. Acute i.v. insulin administration causes a rapid drop in glucose levels an increase in cFos activation in hypothalamic hypocretin neurons and cortisol. We will use insulin infusions to naturally increase hypocretin activity. Aim 1b: Determine the effects of insulin-induced hypocretin activation on hypocretin levels, the appetitive and consummatory aspects of responding for banana-flavored food pellets, and if the effects can be attenuated by a hypocretin-1 antagonist. Aim 2: Determine the effects of a hypocretin-1 antagonist and agonist and agonist/antagonist combinations on the appetitive and consummatory aspects of cocaine self-administration and responding for candy by rhesus monkeys, and determine if the effects of a stressor can be attenuated by a hypocretin-1 antagonist. Our second goal is to examine the effects of hypocretin manipulations on reinstatement of responding reinforced by cocaine and candy. We will use a choice procedure in which monkeys choose to take candy or self-administer cocaine. Aim 3: Determine if a hypocretin-1 antagonist can block reinstatement of responding previously reinforced with cocaine or candy in rhesus monkeys induced by 1) a hypocretin-1 agonist; 2) insulin-induced hypocretin activation; 3) cues paired with the commodity; and 4) the commodity itself. A choice procedure will allow us to demonstrate the selectivity of reinstatement blockade by the antagonist. Impact: Because the hypocretin system plays a complex modulatory role in a wide range of behaviors, we believe that this 2-step approach of first analyzing non-specific, incentive effects of hypocretin manipulations and then the specific effects of a hypocretin antagonist on drug reinstatement will provide the basis for using hypocretins as a novel therapeutic approach for drug abuse, as well as eating disorders. PUBLIC HEALTH RELEVANCE: Hypocretins, by virtue of their involvement in a wide range of behaviors, e.g., drug taking, arousal, provide a novel arena for medication development. Improved medications for drug abuse will have immediate clinical impact.

描述（由申请人提供）：神经肽抑制素-1和-2（De Lecea等，1998）也称为orexin -a和-b（Sakurai等，1998），源自整个大脑的下丘脑和项目。低载素在调节唤醒，对啮齿动物的食物，对压力以及学习和记忆的反应中起作用。降钙蛋白还通过调节药物增强的行为发挥作用1）使用条件位置偏好模型评估的刺激的显着性，2）重复给药后对药物的反应幅度，即敏化和3）环境线索的能力和压力在重复模型中恢复重新定位的能力。这些数据表明，降骨素介导的唤醒具有激励作用，并增加了与增强相关的提示的显着性。鉴于饮食失调和可卡因依赖性的社会问题，对降压素激动剂和拮抗剂对非人类灵长类动物中可卡因和寻求食物和自我管理的影响的仔细评估非常重要。 AIM 1A：确定低载素-1拮抗剂，激动剂和激动剂/拮抗剂组合对6位恒河猴对香蕉味的食物颗粒做出反应的食欲和完整方面的影响。急性I.V.胰岛素给药会导致葡萄糖水平迅速下降，因此下丘脑下腔蛋白神经元和皮质醇的CFO激活增加。我们将使用胰岛素输注来自然增加低载素活性。 AIM 1B：确定胰岛素诱导的降骨素激活对降压素水平的影响，对香蕉味的食物颗粒的反应性和完整性方面，如果降压素-1拮抗剂可以减弱这种作用。 目标2：确定低载素-1拮抗剂，激动剂和激动剂/拮抗剂组合对可卡因自我给药的起伏和完整方面的影响，并通过恒河猴对糖果做出响应，并确定是否可以通过降压蛋白-1拮抗剂减轻压力的影响。 我们的第二个目标是检查降骨素操纵对可卡因和糖果加强反应的恢复作用的影响。我们将使用一个选择程序，其中猴子选择服用糖果或自助式可卡因。 AIM 3：确定降骨素-1拮抗剂是否可以阻止恢复原先用可卡因或糖果在恒河猴中加强的响应。 2）胰岛素诱导的低载糖激活； 3）与商品配对的提示； 4）商品本身。选择程序将使我们能够证明拮抗剂的恢复原始封锁的选择性。影响：由于次生素系统在广泛的行为中起着复杂的调制作用，因此我们认为，首先分析非螺替素操纵的非特异性，激励效果的两步方法，然后降低药物对药物恢复的特定作用将为使用新型治疗素的药物滥用方法提供基础，并消耗药物滥用剂，以及消耗药物滥用的方法。 公共卫生相关性：下胚蛋白，由于它们参与了广泛的行为，例如吸毒，唤醒，为药物开发提供了一种新颖的领域。改善药物滥用的药物将立即产生临床影响。