Neuroimaging of Benzodiazepine-Induced Amnesia

苯二氮卓类药物引起的遗忘症的神经影像学

• 批准号: 6523320
• 负责人: MIRIAM Z. MINTZER
• 金额: $ 32.7万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6523320
• 关键词: behavioral /social science research tag; benzodiazepines; bioimaging /biomedical imaging; blood flow measurement; blood tests; brain circulation; chemical structure function; clinical research; drug abuse; drug administration rate /duration; drug adverse effect; human subject; inhibitor /antagonist; memory disorders; neurochemistry; neuroimaging; neuropharmacology; neuropsychological tests; neuropsychology; pathologic process; positron emission tomography; scopolamine; substance abuse related behavior; triazolam; urinalysis

DESCRIPTION: (provided by applicant) There is concern about the abuse and long term use of benzodiazepine anxiolytic/hypnotic drugs by polydrug abusers and patients. One of the most insidious adverse effects of benzodiazepines is a profound impairment in the ability to form memories of personally experienced events (episodic memory encoding). This project will characterize the changes in brain activity reliably associated with benzodiazepine-induced impairment of episodic memory encoding by parametrically manipulating the level of impairment, and will examine the pharmacological and neurochemical mechanisms underlying these changes. Three double blind, placebo-controlled, within-subject outpatient studies in healthy volunteers are proposed, employing well-established methods in cognitive neuroscience. Following acute drug administration, brain activity associated with performance of a verbal episodic memory encoding task will be measured by regional cerebral blood flow (rCBF) using positron emission tomography (PET) with 15O-H20. Experiment 1 will manipulate the level of encoding impairment via administration of three dose levels of the benzodiazepine hypnotic triazolam. Experiment 2 will manipulate the level of encoding impairment via conjoint administration of triazolam and the benzodiazepine receptor specific antagonist flumazenil, which has been shown to reverse benzodiazepine-induced amnesia; this experiment will also provide information about the pharmacological mechanisms underlying benzodiazepine-induced changes in rCBF during encoding. Experiment 3 will provide information about the neurochemical specificity of benzodiazepine-induced changes in rCBF during encoding by comparing the pattern of rCBF changes produced by triazolam to that produced by scopolamine, a compound which induces comparable decrements in episodic memory encoding but which acts via different receptor site/neurochemical mechanisms. Results of this project will enhance the understanding of the brain mechanisms underlying a serious adverse effect of a widely prescribed and abused class of drugs. Ultimately, data from this research may contribute to the development of new classes of anxiolytic/hypnotic compounds with reduced memory impairing potential, as well as compounds which act to reverse the memory-impairing effects of benzodiazepines. Results of the proposed research also will enhance the understanding of the functional neuroanatomy of basic human memory processes.

描述：（申请人提供） 人们对苯二氮卓类药物的滥用和长期使用表示关注 滥用多种药物者和病人使用的抗焦虑/催眠药物。一个最 苯二氮卓类药物的潜在副作用是对 对个人经历的事件形成记忆的能力（情景记忆 编码）。这个项目将描述大脑活动的变化 与苯二氮卓类药物诱导的情景记忆损害可靠相关 通过参数化地操纵损伤水平来编码，并且将 研究这些潜在的药理学和神经化学机制， 变化3例双盲、安慰剂对照、受试者内门诊患者 建议在健康志愿者中进行研究，采用成熟的方法 在认知神经科学中。急性给药后， 与言语情景记忆编码任务的表现相关的 使用正电子发射通过局部脑血流量（rCBF）测量 使用15 O-H2O进行断层扫描（PET）。实验1将操纵 通过给予三种剂量水平的 苯二氮卓类催眠药三唑仑。实验2将操纵 通过三唑仑和药物联合给药引起的编码障碍 苯二氮卓受体特异性拮抗剂氟马西尼已被证明 逆转苯二氮卓诱导的健忘症;这个实验也将提供 关于潜在药理学机制的信息 benzodiazepine诱导的编码过程中rCBF的变化。实验3将 提供有关神经化学特异性的信息， 苯二氮卓类药物在编码过程中引起的rCBF变化， 三唑仑引起的rCBF变化与东莨菪碱引起的rCBF变化的比值为1/2， 一种化合物，它诱导情景记忆编码的可比性下降， 其通过不同的受体位点/神经化学机制起作用。结果 该项目将增强对大脑机制的理解， 一种被广泛处方和滥用的药物的严重副作用。 最终，这项研究的数据可能有助于开发新的 具有减少记忆损害的抗焦虑/催眠化合物的类别 潜在的，以及化合物的作用，以扭转记忆损害 benzodiazepines的作用拟议研究的结果也将提高 对人类基本记忆的功能性神经解剖学的理解 流程.