Preclinical Synthetic Cannabinoid Vapor Inhalation: Acute and Chronic Effects

 说明(申请人提供)：合成大麻素(SC)的使用，通常被称为“香料”，正在以惊人的速度增加。尽管干细胞在人类中的使用如此广泛，但还没有研究直接调查干细胞在实验动物中的滥用倾向。 我们建议在男性和女性非人灵长类动物(NHP)中进行研究，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。我们的提议的临床意义通过我们在自我给药范例中使用大麻素蒸气来加强；这是与人类大麻素滥用最相关的给药途径。目标1a。增强功效：使用我们已建立的蒸汽自我给药方法，比较THC和JWH-018蒸汽的增强效果。目标1b。毒品替代。通过检查3个SC和THC在一组被训练为吸入THC的猴子和另一组被训练为吸入JWH-018的猴子中维持自我管理的能力，确定THC自我给药的历史是否影响SC的自我给药。目的2.用药模式：使用我们已建立的蒸汽和非药物选择程序，建立探索大麻类药物使用障碍(CUD)药物疗法的范例。1)一种促进催产素释放的化合物(SOC1)，2)一种下丘脑泌素拮抗剂(SB334867)，以及3)作为阳性对照，CB1拮抗剂利莫那班将在接受过自我给药THC训练的猴子和接受过自我给药JWH-018训练的猴子身上进行比较。目的3.慢性暴露：建立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。在确定了生理的剂量-反应函数，例如心率，以及SCS和THC的作用效果后，我们将让动物每天三次暴露于相同剂量的4种药物，持续4周(1种药物/阶段)。我们将在4种药物的开始和4周结束时测量利莫那班催促停药的效果。目的4.新化合物评估：鉴于新干细胞的不断发展，将对一组猴子进行训练，以评估在最初2.5年中出现的最多3种新干细胞的增强效果 否则我们将测试目前在香料中发现的其他化合物，这些化合物出现的频率增加。影响：SC的使用是一个公共卫生问题，可获得的临床前数据最少。拟议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物种(非人类灵长类动物)和给药途径(蒸汽吸入)中的风险的认识上的一个关键空白。这些发现将1)告知和预测与SCs相关的风险，当它们出现在药物市场上；2)建立一个临床前模型，用于测试CUD和SC障碍的潜在治疗方法；3)为使用日益流行的蒸汽输送途径，即“蒸发”的实验室研究提供方法。

 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."