Benzodiazepine Use/Abuse: Effects on Memory Mechanisms

描述（由申请方提供）：关注患者和多种药物滥用者长期使用和滥用苯二氮卓类抗焦虑/催眠药物。苯二氮卓类药物最潜在的副作用之一是记忆障碍。五个双盲，安慰剂对照的门诊实验，建议在健康志愿者中测试特定的假设，急性和慢性影响的苯二氮卓类药物对记忆过程，指导下，在人类记忆研究的最新概念和方法的发展。实验1将检验苯二氮卓类药物选择性损害工作记忆中涉及的特定过程的假设（一种短期记忆，能够在服务于行为目标的过程中对信息进行临时维护和在线操作，并且对于许多高阶认知功能的表现至关重要），苯二氮卓诱导的工作记忆损伤与抗胆碱能药物东莨菪碱诱导的工作记忆损伤在性质上不同。实验2和3将测试的假设，苯二氮卓类药物选择性地损害特定的过程中涉及元记忆（人们的知识和意识，他们自己的记忆;一个基本的先决条件，以获取新的信息和修改一个人的行为），苯二氮卓类药物诱导的元记忆损伤从性质上不同于东莨菪碱和酒精诱导。实验4将通过检查苯二氮卓类催眠药三唑仑的遗忘作用与镇静作用的变化，作为不同剂量的兴奋剂d-苯丙胺联合不同剂量的三唑仑给药的函数，来检验苯二氮卓类药物的记忆损害作用可以与药物的镇静作用分离的假设。实验5将通过检查苯二氮卓类药物重复给药过程中耐受性对镇静作用与记忆作用的差异程度，检验遗忘作用与镇静作用分离的假设;结果还将提供与苯二氮卓类药物长期使用者直接临床相关的信息。除了增强对苯二氮卓类药物诱导的健忘症及其神经化学特异性的理解外，来自这个新颖项目的数据将独特地结合药理学和认知操作，将有助于更好地理解人类记忆过程的特异性以及记忆和唤醒之间的关系。该项目的信息还可用于制定认知康复计划，并根据长期使用者的具体能力定制药物滥用和焦虑治疗干预措施。

DESCRIPTION (provided by applicant): There is concern about the long-term use and abuse of benzodiazepine anxiolytic/hypnotic drugs by patients and polydrug abusers. One of the most insidious adverse effects of benzodiazepines is memory impairment. Five double-blind, placebo-controlled outpatient experiments are proposed in healthy volunteers to test specific hypotheses regarding the acute and chronic effects of benzodiazepines on memory processes, guided by recent conceptual and methodological developments in human memory research. Experiment 1 will test the hypothesis that benzodiazepines selectively impair specific processes involved in working memory (a type of short-term memory that enables the temporary maintenance and on-line manipulation of information in the service of behavioral goals, and is critical for the performance of many higher-order cognitive functions), and that the benzodiazepine-induced working memory impairment differs qualitatively from that induced by the anticholinergic drug scopolamine. Experiments 2 and 3 will test the hypothesis that benzodiazepines selectively impair specific processes involved in metamemory (people's knowledge and awareness of their own memory; a fundamental prerequisite to acquiring new information and modifying one's behavior), and that the benzodiazepine-induced metamemory impairment differs qualitatively from that induced by both scopolamine and alcohol. Experiment 4 will test the hypothesis that the memory-impairing effects of benzodiazepines can be dissociated from the drugs' sedative effects by examining changes in the benzodiazepine hypnotic triazolam's amnestic versus sedative effects as a function of administration of varying doses of the stimulant d-amphetamine, conjointly with varying doses of triazolam. Experiment 5 will test the hypothesis regarding dissociation of amnestic versus sedative effects by examining the degree to which tolerance, over the course of repeated benzodiazepine administration, develops differentially to effects on sedation vs. memory; results will also provide information of direct clinical relevance to long-term benzodiazepine users. In addition to enhancing the understanding of benzodiazepine-induced amnesia and its neurochemical specificity, data from this novel project, which uniquely combines pharmacological and cognitive manipulations, will contribute to a better understanding of the specificity of human memory processes and of the relationship between memory and arousal. Information from this project can also be used to develop cognitive rehabilitation programs and to tailor drug abuse and anxiety treatment interventions to the specific capabilities of long-term users.