Preclinical Synthetic Cannabinoid Vapor Inhalation: Acute and Chronic Effects

 描述（由申请人提供）：合成大麻素（SC），通常被称为“香料”，正在以惊人的速度增加。尽管如此广泛的人类使用，但还没有研究直接调查SC在实验室动物中的滥用倾向。 我们建议在雄性和雌性非人灵长类动物（NHP）中进行研究，以评估3种SC（JWH 018，JWH-073和HU-210）相对于δ 9-四氢大麻酚（THC）的行为和生理风险。我们的建议的临床意义是通过我们在自我管理模式中使用大麻素蒸汽来增强的;管理途径与人类大麻素滥用最相关。目标1a。强化功效：使用我们建立的蒸汽自我给药方法比较THC和JWH-018蒸汽的强化效果。目标1b。药物替代。通过在一组训练吸入THC的猴子和另一组训练吸入JWH-018的猴子中检查3种SC和THC维持自我施用的能力来确定THC自我施用史是否影响SC自我施用。目标2.用药模式：使用我们建立的蒸汽与非药物选择程序，建立一个探索大麻素使用障碍（CUD）药物治疗的范例。将在训练以自我施用THC的猴子和训练以自我施用JWH-018的猴子中比较1）增加催产素释放的化合物（SOC 1）、2）下丘脑泌素拮抗剂（SB 334867）和3）作为阳性对照的CB 1拮抗剂利莫那班的作用。目标3：慢性暴露：建立长期暴露于实验者递送的JWH-018、JWH-073、HU-210和THC蒸气的生理和行为效应。在确定生理学的剂量反应函数之后，例如，心率以及SC和THC的操作性效应，我们将动物暴露于等效剂量的4种药物，每天三次，持续4周（1种药物/阶段）。我们将在4周开始和结束时测量4种药物中每一种的利莫那班促停作用。目标4。新化合物评价：考虑到新的SC的持续发展，将训练一组猴子来评估在前2.5年内出现的多达3种新的SC的强化作用。 或者我们将测试目前在Spice中发现的出现频率增加的其他化合物。影响：SC使用是一个公共卫生问题，可获得的临床前数据很少。拟定的研究旨在填补我们对这些药物在具有直接临床相关性的种属（非人灵长类动物）和给药途径（蒸汽吸入）中的风险的认识方面的关键空白。这些发现将1）告知和预测与SC相关的风险，因为它们出现在药物市场上，2）建立临床前模型，用于测试CUD和SC疾病的潜在治疗方法，以及3）提供使用越来越流行的蒸汽输送途径的实验室研究方法，即，“vaping. "

 DESCRIPTION (provided by applicant): The use of synthetic cannabinoids (SC), commonly referred to as `Spice,' is increasing at an alarming rate. In spite of such widespread human use there have been no studies directly investigating the abuse liability of SCs in laboratory animals. We propose studies in male and female non-human primates (NHPs) to assess the behavioral and physiological risks of 3 SCs (JWH018, JWH-073, and HU-210) relative to delta9-tetrahydrocannabinol (THC). The clinical significance of our proposal is enhanced by our use of cannabinoid vapors in a self-administration paradigm; the administration route most relevant to human cannabinoid abuse. Aim 1a. Reinforcing Efficacy: Compare the reinforcing effects of THC and JWH-018 vapors using our established methods of vapor self-administration. Aim 1b. Drug Substitution. Determine if a history of THC self-administration affects SC self-administration by examining the ability of 3 SCs and THC to maintain self- administration in one group of monkeys trained to inhale THC and in another group of monkeys trained to inhale JWH-018. Aim 2. Medication Model: Establish a paradigm for probing pharmacotherapies for cannabinoid-use disorders (CUD) using our established vapor vs. non-drug choice procedures. The effects of 1) a compound that increases oxytocin release (SOC1), 2) a hypocretin antagonist (SB334867), and 3), as a positive control, the CB1 antagonist rimonabant will be compared in monkeys trained to self-administer THC and monkeys trained to self-administer JWH-018. Aim 3. Chronic Exposure: Establish the physiological and behavioral effects of chronic exposure to experimenter-delivered JWH-018, JWH-073, HU-210, and THC vapor. After determining dose-response functions for physiological, e.g., heart rate, and operant effects of the SCs and THC, we will expose animals to equipotent doses of the 4 drugs thrice a day for 4 weeks (1 drug/phase). We will measure the effects of rimonabant-precipitated withdrawal at the beginning and at the end of 4 weeks for each of the 4 drugs. Aim 4. Novel Compound Evaluation: Given the continuous development of new SCs, one group of monkeys will be trained to assess the reinforcing effects of up to 3 novel SCs that emerge over the first 2.5 years of this proposal, or we will test other compounds currently identified in Spice that appear with increased frequency. Impact: SC use is a public health concern with minimal preclinical data available. The proposed studies are designed to fill a critical gap in our knowledge regarding the risks of these drugs in a species (non-human primates) and route of administration (vapor inhalation) with direct clinical relevance. The findings will 1) inform and predict the risks associated with SCs as they emerge on the drug market, 2) establish a preclinical model for testing potential therapeutic approaches for CUD and SC disorders, and 3) provide methods for laboratory studies using the increasing popular route of vapor delivery, i.e., "vaping."