Hypocretin Antagonists as a Novel Approach to Medication Development

描述（由申请人提供）：神经肽下丘脑-1和-2 （de Lecea et al., 1998）也被称为食欲素- a和-B （Sakurai et al., 1998）来源于外侧下丘脑，并贯穿整个大脑。下丘脑泌素在调节唤醒、啮齿动物觅食、对压力的反应以及学习和记忆方面发挥作用。下丘脑泌素还在药物强化行为中发挥作用，通过调节1)使用条件-地点偏好模型评估的与药物配对的刺激的显著性，2)重复给药后对药物的反应的大小，即致敏，以及3)环境线索和压力在复发模型中引发恢复的能力。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著性。鉴于饮食失调和可卡因依赖的社会问题，仔细控制评估下丘脑促分泌素激动剂和拮抗剂对非人类灵长类动物可卡因和食物寻找和自我管理的影响是非常重要的。目的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食欲方面的影响。急性静脉注射胰岛素导致葡萄糖水平迅速下降，下丘脑下丘脑下丘脑分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地增加下丘脑泌素的活性。目的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食欲方面的反应，以及下丘脑分泌素-1拮抗剂是否可以减弱这种影响。目的2：确定下丘脑泌素-1拮抗剂和激动剂以及激动剂/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满足方面的影响，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分泌素的操作对可卡因和糖果增强的反应的恢复的影响。我们将使用一种选择程序，让猴子选择吃糖果还是自己服用可卡因。目的3：确定下丘脑分泌素-1拮抗剂是否可以阻断先前用可卡因或糖果诱导的恒河猴反应的恢复1)下丘脑分泌素-1激动剂；2)胰岛素诱导的下丘脑分泌素激活；3)与商品配对的线索；第四，商品本身。选择程序将使我们能够证明拮抗剂恢复阻断的选择性。影响：由于下丘脑分泌素系统在广泛的行为中起着复杂的调节作用，我们相信这种先分析下丘脑分泌素操纵的非特异性激励作用，然后分析下丘脑分泌素拮抗剂对药物恢复的特异性作用的两步方法将为利用下丘脑分泌素作为药物滥用和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.