Treatment of Cannabinoid Withdrawal in Rhesus Monkeys

描述（由申请人提供）：越来越多地报告了马里布汀依赖和戒断，但尚未确定适当的治疗方案。该R 01将在一项令人信服的研究基础上进行扩展，该研究表明，药物辨别可用于量化大麻素拮抗剂SR 141716 A对接受delta 9-THC的猴子的行为影响。依赖性将通过delta 9-THC和戒断建立，戒断特征为直接可观察到的体征、药物辨别和神经内分泌反应。目的1将检查大麻素和单胺在由SR 141716 A和暂时停止A9-THC治疗诱导的delta 9-THC戒断的辨别性刺激效应中的作用。研究将检查大麻素和单胺在SR 141716 A诱导的直接可观察到的戒断体征中的作用。总的来说，目标1中的研究将检查大麻素和单胺在不同戒断指数中的相对贡献，并将检验单胺减弱区分性措施而不是其他戒断指数的假设。目的2将检查下丘脑垂体肾上腺活动（以皮质醇和ACTH为指标）在delta 9-THC的急性和慢性效应中的作用，并将检查CRH拮抗剂在修改delta 9-THC戒断中的作用。目标3中将使用药物辨别来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的辨别刺激作用的修饰，以及大麻素拮抗剂对这些辨别刺激作用的阻断。一个可能的未来方向将是描述吸入大麻烟雾的依赖性。该应用程序将解决需要了解大麻素依赖的行为，药理学和神经内分泌决定因素，并将检查测试化合物的大麻素戒断和急性大麻行动的修改。

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.