Preclinical Synthetic Cannabinoid Vapor Inhalation: Acute and Chronic Effects

临床前合成大麻素蒸气吸入：急性和慢性影响

基本信息

批准号：
8859590
负责人：
ZIVA D COOPER
金额：
$ 70.87万
依托单位：
NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8859590
关键词：
Acute Affect Agonist Animals Behavioral Blood Pressure Breathing CNR1 gene Cannabinoids Cannabis Chronic Clinical Data Development Disease Dose Employee Strikes Evaluation Exposure to Female Food Frequencies Health Heart Rate Human Illicit Drugs Kidney Knowledge Laboratory Animals Laboratory Study Learning Macaca mulatta Marijuana Marijuana Dependence Marketing Measures Methods Modeling Monkeys Oxytocin Pharmaceutical Preparations Pharmacology Pharmacotherapy Phase Physiological Pre-Clinical Model Procedures Public Health Recording of previous events Relative (related person)Research Design Risk Route Self Administration Self-Administered Smoke Spices Telemetry Testing Tetrahydrocannabinol Therapeutic Training Withdrawal attenuation base clinically relevant clinically significant comparative efficacy design drug market drug testing hypocretin male nephrotoxicity non-drug nonhuman primate novel pre-clinical preclinical study public health relevance receptor response rimonabant synthetic cannabinoid vaping vapor

项目摘要

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."

描述（由适用提供）：使用合成大麻素（SC）的使用，通常称为“香料”，以惊人的速度增加。尽管人类使用了这种宽度，但仍未直接研究实验动物中SC的滥用责任。我们建议对男性和女性非人类隐私（NHP）进行研究，以评估相对于delta9-tetrahydrocanbinol（thc），相对于Delta9-tahydrocantabinol（THC），相对于Delta9-四氢甲醇（THC），您的行为和物理风险（JWH018，JWH-073和HU-210）的行为和身体风险。通过在自我管理范式中使用大麻素蒸气，我们的提案的临床意义增强了。行政管理路线与人类大麻素滥用最相关。目标1a。增强功效：使用我们既定的蒸气自我给药方法比较THC和JWH-018蒸气的增强作用。目标1B。毒品替代。确定THC自我管理的历史是否通过检查3 SC和THC在一组受吸入THC的猴子和受过训练的in Hale in Hale JWH-018训练的猴子中维持自我管理的能力来影响SC自我管理。 AIM 2。药物模型：建立一个用于使用我们已建立的蒸气与非药物选择程序探测大麻素疾病（CUD）的药物疗法的范例。 1）1）增加氧气释放的化合物（SOC1），2）降压素拮抗剂（SB334867），而3）作为阳性对照，CB1拮抗剂Rimonabant将在经过培训的猴子中进行比较，以自助训练为自动化的THC和猴子，从而受过训练的训练为自动化的Monkeys训练了自我adadMinister jwh-wher jwh-018。 AIM 3。慢性暴露：建立长期暴露于实验者转移的JWH-018，JWH-073，HU-210和THC Vapor的身体和行为影响。在确定了SC和THC的生理（例如心率和手术作用）的剂量反应功能之后，我们将使动物每天三分之一的药物的等效剂量持续4周（1个药物/相）。我们将在四种药物的开始和4周结束时衡量三班班症的戒断的影响。 AIM 4。新颖的复合评估：鉴于新SC的持续发展，将对一组猴子进行培训，以评估最多3个新颖SC的增强作用，这些SC在最初的2.5年中出现在该建议中，我们将测试当前在香料中鉴定出的其他化合物，这些化合物的频率增加。影响：SC的使用是公共卫生的关注点，最少可用的临床前数据。拟议的研究旨在填补有关这些药物在某种物种（非人类隐私）和给药途径（蒸气吸入）中具有直接临床相关性的重要差距。研究结果将为1）在药物市场上出现时提供并预测与SC相关的风险，2）建立一个临床前模型，用于测试CUD和SC疾病的潜在治疗方法，以及3）使用蒸气量增加的流行途径为实验室研究提供方法，即“ vaping”。