Preclinical Synthetic Cannabinoid Vapor Inhalation: Acute and Chronic Effects

 描述（由申请人提供）：合成大麻素（SC）（通常称为“香料”）的使用正在以惊人的速度增加。尽管人类使用如此广泛，但尚未有研究直接调查 SC 在实验动物中的滥用倾向。 我们建议对雄性和雌性非人类灵长类动物 (NHP) 进行研究，以评估 3 种 SC（JWH018、JWH-073 和 HU-210）相对于 delta9-四氢大麻酚 (THC) 的行为和生理风险。我们在自我管理模式中使用大麻素蒸气增强了我们建议的临床意义；与人类大麻素滥用最相关的给药途径。目标 1a。增强功效：使用我们既定的蒸气自我管理方法比较 THC 和 JWH-018 蒸气的增强效果。目标 1b。药物替代。通过检查一组接受过吸入 THC 训练的猴子和另一组接受过吸入 JWH-018 训练的猴子中 3 个 SC 和 THC 维持自我给药的能力，确定 THC 自我给药史是否影响 SC 自我给药。目标 2. 药物模型：使用我们既定的蒸气与非药物选择程序建立一个探索大麻素使用障碍 (CUD) 药物疗法的范例。将在经过自我施用 THC 训练的猴子和经过自我施用 JWH-018 训练的猴子中比较 1) 增加催产素释放的化合物 (SOC1)、2) 下丘脑分泌素拮抗剂 (SB334867) 和 3) 作为阳性对照的 CB1 拮抗剂利莫那班的效果。目标 3. 长期暴露：确定长期暴露于实验者提供的 JWH-018、JWH-073、HU-210 和 THC 蒸气的生理和行为影响。在确定 SC 和 THC 的生理（例如心率）和操作效果的剂量反应函数后，我们将让动物接触等量剂量的 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 种药物中每种药物利莫那班突然戒断的效果。目标 4. 新型化合物评估：鉴于新 SC 的不断开发，将训练一组猴子来评估前 2.5 年内出现的最多 3 种新型 SC 的增强效果 该提案的一部分，或者我们将测试目前在 Spice 中发现的其他出现频率增加的化合物。影响：SC 的使用是一个公共卫生问题，可用的临床前数据很少。拟议的研究旨在填补我们对这些药物在物种（非人类灵长类动物）中的风险和具有直接临床相关性的给药途径（蒸气吸入）的认识的关键空白。研究结果将 1) 告知和预测 SC 在药品市场上出现时的相关风险，2) 建立临床前模型，用于测试 CUD 和 SC 疾病的潜在治疗方法，3) 提供使用日益流行的蒸汽输送途径（即“电子烟”）进行实验室研究的方法。

 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."