Neuroimaging of Benzodiazepine-Induced Amnesia

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担忧 多药滥用者和患者使用的抗焦虑/催眠药物。其中最 苯二氮卓类药物的潜在不良反应是对 对亲身经历的事件形成记忆的能力(情节记忆 编码)。这个项目将描述大脑活动的变化。 与苯二氮类药物引起的情景记忆障碍可靠相关 通过参数操作损伤程度进行编码，并将 检查其背后的药理学和神经化学机制 改变。三名双盲、安慰剂对照、受试者内的门诊患者 建议对健康志愿者进行研究，采用成熟的方法。 在认知神经科学方面。在急性给药后，大脑活动 与言语情景记忆编码任务相关的任务将是 用正电子发射测量局部脑血流量 15O-H20断层扫描(PET)。实验1将操纵 通过给药三个剂量水平的 苯二氮卓类催眠药三唑仑。实验2将操纵 三唑仑联合应用对损伤进行编码 苯二氮卓类受体特异性拮抗剂氟马西尼，已被证明 逆转苯二氮类药物引起的遗忘；这项实验还将提供 关于潜在的药理机制的信息 苯二氮卓类药物在编码过程中引起rCBF的变化。实验3将 提供有关神经化学特异性的信息 通过比较模式比较苯二氮类药物在编码过程中诱导rCBF的变化 三唑仑引起的rCBF变化与东莨菪碱引起的rCBF变化相比，a 一种化合物，在情景记忆编码中引起类似的减少，但 它通过不同的受体位置/神经化学机制起作用。结果： 这个项目将加强对大脑机制的理解 一种广泛处方和滥用的药物的严重不良反应。 最终，这项研究的数据可能有助于开发新的 降低记忆损害的抗焦虑/催眠化合物类 潜力，以及能逆转记忆受损的化合物 苯二氮卓类药物的作用。拟议的研究结果也将增强 对人类基本记忆功能神经解剖学的认识 流程。

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.