Hypocretin Antagonists as a Novel Approach to Medication Development

描述（由申请人提供）：神经肽下丘脑泌素-1和-2（de Lecea等人，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大脑。下丘脑泌素在调节啮齿动物的觉醒、觅食、应激反应以及学习和记忆中起作用。下丘脑泌素还通过调节1）与药物配对的刺激的显著性，如使用条件-位置偏好模型评估的，2）重复给药后对药物的反应的幅度，即，致敏，以及3）环境线索和压力在复发模型中引起恢复的能力。这些数据表明，下丘脑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，仔细控制评估下丘脑泌素激动剂和拮抗剂对非人灵长类动物中可卡因和食物寻求以及自我给药的影响是非常重要的。 目标1a：通过6只恒河猴确定下丘脑泌素-1拮抗剂、激动剂和激动剂/拮抗剂组合对香蕉味食物颗粒的食欲和消耗方面的反应的影响。急性静脉注射胰岛素导致葡萄糖水平迅速下降，下丘脑泌素神经元和皮质醇中cFos激活增加。我们将使用胰岛素输注来自然增加下丘脑泌素活性。目标1b：确定胰岛素诱导的下丘脑分泌素激活对下丘脑分泌素水平的影响，对香蕉味食物颗粒的食欲和消费方面的反应，以及下丘脑分泌素-1拮抗剂是否可以减弱这种影响。 目标二：确定下丘脑泌素-1拮抗剂和激动剂和激动剂/拮抗剂组合对恒河猴可卡因自我给药和糖果反应的食欲和消费方面的影响，并确定下丘脑泌素-1拮抗剂是否可以减弱应激源的影响。 我们的第二个目标是检查下丘脑泌素操作对可卡因和糖果强化的反应恢复的影响。我们将使用一个选择程序，让猴子选择吃糖果或自己服用可卡因。目标3：确定下丘脑泌素-1拮抗剂是否可以阻断由1）下丘脑泌素-1激动剂; 2）胰岛素诱导的下丘脑泌素激活; 3）与商品配对的提示;以及4）商品本身诱导的恒河猴中先前用可卡因或糖果增强的反应的恢复。选择程序将使我们能够证明拮抗剂对恢复性阻断的选择性。影响：由于下丘脑泌素系统在广泛的行为中起着复杂的调节作用，我们认为，这种两步法首先分析下丘脑泌素操纵的非特异性激励作用，然后分析下丘脑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以及饮食失调的新治疗方法提供基础。

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.