CLIN & NEUROBIOL EFFECTS OF CANNABIS DEPENDENCE IN YOUNG ADULTS

大麻依赖仍然是30岁以下年轻人的一个主要公共卫生问题。一 原因可能是大麻的使用降低了执行功能，造成了无法抑制的脆弱性 适应不良的行为，如吸毒。我们的假设是，更严重的大麻 依赖在临床上与神经心理任务中更严重的损害有关，包括 执行职能，整个中心的运作定义为精神控制、主动性和流畅性、自我监控、 工作记忆和注意力，以及抑制。 具体目标#1：描述大麻依赖的严重程度对主观(如焦虑、渴望)的影响 和目标(例如，血浆ACTH、皮质醇、MHPG)措施使用以下催促戒断 成年志愿者服用CBI大麻素受体拮抗剂、利莫那班或安慰剂 大麻依赖的双盲随机设计。THC浓度和神经化学物质 在成分3中，平行的情绪戒断措施可能为临床前研究提供信息 和4.具体目标#2：确定CANTAB任务中损伤的存在和持续性 年轻人的执行功能与大麻依赖严重程度的关系(见具体目标1) 有大麻依赖的志愿者与正常对照组相比。具体目标#3：确定存在 与大麻依赖严重程度相关的大脑活动异常的持续性(见具体目标 #1)在组件2中使用与Tapert博士共同开发的额叶皮质功能探针的功能磁共振成像。 为了实现这些目标，将进行一项为期28天的纵向研究，主要包括两个部分：1)一个 单剂量、双盲、安慰剂对照的实验室大麻沉淀性戒断研究 使用CBI受体拮抗剂利莫那班90 mg，口服，然后每周评估KEY 自然主义背景下的大麻戒断症状，以及2.神经心理评估与功能磁共振成像 任务刺激被选择为对大麻相关损害的敏感性，在第一次和 在一个自然主义的环境中进行了28天的禁欲监测之后。研究对象为40名年轻人 与大麻成瘾和20个人口统计相似的不使用对照。与 中心的翻译目标，任务来源于剑桥神经心理测试 自动化电池(Cantag)允许与研究中研究的非人类灵长类进行跨物种比较 组件3(Taffe)和组件2(Tapert)中的青少年。平行青少年之间独特的合作 非人灵长类动物项目将促进该中心确定神经生物学的总体目标 大麻暴露的发展阶段和模式交叉损害的机制 执行认知功能，从而增加对大麻依赖的脆弱性。

Cannabis dependence remains a major public health problem in young adults under 30 years of age. One reason may be that cannabis use decreases executive functioning, creating a vulnerability to fail to inhibit maladaptive behaviors, such as using drugs. It is our hypothesis that greater severity of cannabis dependence is associated clinically with greater severity of impairment on neuropsychological tasks involving executive functioning, operationally defined center-wide as mental control, initiative and fluency, selfmonitoring, working memory and attention, and inhibition. Specific Aim # 1: To characterize the severity of cannabis dependence on subjective (e.g., anxiety, craving) and objective (e.g. plasma ACTH, cortisol, MHPG) measures using precipitated withdrawal following administration of the CBI cannabinoid receptor antagonist, rimonabant, or placebo in adult volunteers with cannabis dependence in a double-blind randomized design. THC concentrations and neurochemical measures that parallel emotional measures of withdrawal may inform pre-clinical studies in Components 3 and 4. Specific Aim # 2: To determine the presence and persistence of impairment on CANTAB tasks of executive function relative to severity of cannabis dependence (see Specific Aim # 1) in young adult volunteers with cannabis dependence relative to normal controls. Specific Aim # 3: To identify the presence and persistence of abnormality in brain activity relative to severity of cannabis dependence (see Specific Aim # 1) using fMRI with probes of frontal cortex function developed with Dr. Tapert in Component 2. To accomplish these aims, a 28-day longitudinal study will be conducted with two primary components: 1.) a single-dose, double-blind, placebo-controlled study of precipitated cannabis withdrawal in the laboratory using the CBI receptor antagonist, rimonabant 90 mg po, followed by four weekly assessments of key symptoms of cannabis withdrawal in a naturalistic setting, and 2.) neuropsychological assessment and fMRI with task stimuli selected for sensitivity to cannabis-related impairment, administered on the first and following 28 days of monitored abstinence in a naturalistic environment. Subjects will be 40 young adults with cannabis dependence and 20 demographically similar non-using controls. Consistent with the translational objectives of the Center, tasks are derived from the Cambridge Neuropsychological Test Automated Battery (CANTAB) to permit cross-species comparison with non-human primates studied in Component 3 (Taffe) and teens in Component 2 (Tapert). The unique collaboration between parallel teen and non-human primate projects will facilitate the overall Center objective of identifying neurobiological mechanisms through which developmental stage and pattern of cannabis exposure intersect to impair executive cognitive functioning, thereby increasing vulnerability to cannabis dependence.