Treatment of Cannabinoid Withdrawal in Rhesus Monkeys

说明(申请人提供)：大麻依赖和戒断的报告越来越多，但尚未确定适当的治疗选择。该R01将在一系列令人信服的研究基础上展开，证明药物歧视可用于量化大麻素拮抗剂SR 141716A在接受Delta9-THC治疗的猴子中的行为影响。依赖将通过Delta9-THC和戒断建立，其特征是直接可观察到的体征、药物歧视和神经内分泌反应。目的1研究大麻素和单胺类物质在SR 141716A和暂时停止A9-THC治疗所引起的Delta9-THC戒断的区别性刺激效应中的作用。研究将考察大麻素和单胺类药物在SR 141716A诱导的直接可见戒断迹象中的作用。总的来说，目标1中的研究将审查不同戒断指数中大麻素和单胺类药物的相对贡献，并将检验单胺类药物削弱歧视性措施而不是其他戒断指数的假设。目的2将研究下丘脑垂体肾上腺活动(以皮质醇和ACTH为指标)在Delta9-THC急性和慢性效应中的作用，并将研究CRH拮抗剂在改变Delta9-THC戒断中的作用。目标3将使用药物歧视来描述吸入大麻烟雾的主观影响，大麻烟雾是人类的主要给药途径。研究将审查大麻二酚和大麻酚对吸入大麻烟雾的歧视性刺激效应的修正，以及大麻素拮抗剂对这些歧视性刺激效应的阻断。未来一个可能的方向将是对吸入大麻烟雾的依赖进行表征。这项应用将解决了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，并将检查用于修饰大麻素戒断和急性大麻作用的测试化合物。

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.