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hypocretin-1和-2（de Lecea等，1998）也称为食欲素-A和-B（Sakurai等，1998），源自外侧下丘脑并投射到整个下丘脑。脑。下丘脑分泌素在调节啮齿动物的觉醒、觅食、压力反应以及学习和记忆方面发挥着作用。下丘脑分泌素还通过调节 1) 与药物配对的刺激的显着性（使用条件地点偏好模型评估）在药物强化行为中发挥作用，2) 重复给药后对药物的反应程度，即敏化，以及 3)环境线索和压力引起复发模型恢复的能力。这些数据表明，下丘脑分泌素介导的唤醒具有激励作用，并增加了与强化相关的线索的显着性。考虑到饮食失调和可卡因依赖的社会问题，对下丘脑分泌素激动剂和拮抗剂对非人类灵长类动物的可卡因和食物寻求以及自我给药的影响进行仔细的控制评估非常重要。 目标 1a：确定下丘脑分泌素 1 拮抗剂、激动剂和激动剂/拮抗剂组合对 6 只恒河猴对香蕉味食物颗粒的食欲和完成反应的影响。急性静脉注射施用胰岛素会导致葡萄糖水平迅速下降，下丘脑下丘脑分泌素神经元和皮质醇中的 cFos 激活增加。我们将使用胰岛素输注来自然地增加下丘脑分泌素活性。目标 1b：确定胰岛素诱导的下丘脑泌素激活对下丘脑泌素水平的影响、对香蕉味食物颗粒反应的食欲和完成性方面，以及是否可以通过下丘脑泌素 1 拮抗剂减弱这种影响。 目标 2：确定下丘脑分泌素 1 拮抗剂和激动剂以及激动剂/拮抗剂组合对恒河猴自我施用可卡因的食欲和完成性以及对糖果的反应的影响，并确定压力源的影响是否可以通过以下方法减弱：下丘脑分泌素-1 拮抗剂。 我们的第二个目标是检查下丘脑分泌素操作对恢复可卡因和糖果增强的反应的影响。我们将使用一个选择程序，让猴子选择吃糖果或自我注射可卡因。目标 3：确定下丘脑分泌素 1 拮抗剂是否可以阻止恒河猴先前用可卡因或糖果强化的反应恢复，这些反应是由 1) 下丘脑分泌素 1 激动剂诱导的； 2) 胰岛素诱导的下丘脑分泌素激活； 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恢复封锁的选择性。影响：由于下丘脑分泌素系统在多种行为中发挥着复杂的调节作用，我们认为这种两步法首先分析下丘脑分泌素操作的非特异性激励效应，然后分析下丘脑分泌素拮抗剂对药物恢复的特异性作用将为使用下丘脑泌素作为药物滥用和饮食失调的新治疗方法奠定基础。 公共健康相关性：下丘脑泌素由于参与多种行为，例如吸毒、性唤起，为药物开发提供了一个新的领域。改进药物滥用药物将产生立竿见影的临床影响。