Treatment of Cannabinoid Withdrawal in Rhesus Monkeys

描述（由申请人提供）：大麻依赖和戒断越来越多的报道，但适当的治疗方案尚未确定。该R01将扩展一个令人信服的调查线，证明药物歧视可用于量化大麻素拮抗剂SR 141716A对接受δ 9- thc的猴子的行为影响。对δ 9-四氢大麻酚的依赖和以可直接观察到的体征、药物鉴别和神经内分泌反应为特征的戒断。目的1将研究大麻素和单胺在由SR 141716A和暂时停止A9-THC治疗诱导的delta - 9- thc戒断的区别性刺激效应中的作用。研究将检查大麻素和单胺在SR 141716A诱导的直接可观察到的戒断症状中的作用。总体而言，Aim 1中的研究将检查大麻素和单胺在不同戒断指标中的相对贡献，并将检验单胺减轻歧视性措施而不是其他戒断指标的假设。目的2将研究下丘脑垂体肾上腺活性（以皮质醇和ACTH为指标）在德尔塔9-四氢大麻酚的急性和慢性作用中的作用，并将研究CRH拮抗剂在调节德尔塔9-四氢大麻酚戒断中的作用。药物歧视将在Aim 3中用于表征吸入大麻烟雾的主观影响，这代表了人类的主要给药途径。研究将检查大麻二酚和大麻酚对吸入大麻烟雾的鉴别刺激作用的改变，以及大麻素拮抗剂对这些鉴别刺激作用的阻断。一个可能的未来方向将是描述吸入大麻烟雾产生的依赖性。该应用程序将满足理解大麻素依赖的行为、药理学和神经内分泌决定因素的需要，并将检查测试化合物对大麻素戒断和急性大麻作用的修饰。

DESCRIPTION (provided by applicant): Marijuana dependence and withdrawal are increasingly reported, yet adequate treatment options have not been identified. This R01 will expand upon a compelling line of investigation demonstrating that drug discrimination can be used to quantify the behavioral effects of the cannabinoid antagonist SR 141716A in monkeys receiving delta9-THC. Dependence will be established with delta9-THC and withdrawal characterized by directly observable signs, drug discrimination, and neuroendocrine response. Aim 1 will examine a role for cannabinoid and monoamines in the discriminative stimulus effects of delta9-THC withdrawal, induced both by SR 141716A and by temporary discontinuation of A9-THC treatment. Studies will examine a role for cannabinoids and monoamines in the directly observable signs of withdrawal induced by SR 141716A. Collectively, studies in Aim 1 will examine the relative contribution of cannabinoids and monoamines across different indices of withdrawal and will test the hypothesis that monoamines attenuate discriminative measures and not other indices of withdrawal. Aim 2 will examine a role for hypothalamic pituitary adrenal activity (indexed by cortisol and ACTH) in the acute and chronic effects of delta9-THC and will examine a role for CRH antagonists in modifying delta9-THC withdrawal. Drug discrimination will be used in Aim 3 to characterize the subjective effects of inhaled marijuana smoke which represents the predominant route of administration in humans. Studies will examine modification of the discriminative stimulus effects of inhaled marijuana smoke by cannabidiol and cannabinol and blockade of these discriminative stimulus effects by cannabinoid antagonists. A likely future direction will be to characterize dependence that occurs to inhaled marijuana smoke. This application will address a need for understanding the behavioral, pharmacologic, and neuroendocrine determinants of cannabinoid dependence and will examine test compounds for modification of cannabinoid withdrawal and acute marijuana action.