Benzodiazepine Use/Abuse: Effects on Memory Mechanisms

描述(由申请人提供)：有人关注病人和多药滥用者长期使用和滥用苯二氮卓类抗焦虑/催眠药物。苯二氮类药物最隐蔽的副作用之一是记忆障碍。在人类记忆研究的最新概念和方法发展的指导下，建议在健康志愿者中进行五项双盲、安慰剂对照的门诊试验，以测试关于苯二氮类药物对记忆过程的急性和慢性影响的具体假设。实验1将测试以下假设：苯二氮卓类药物选择性地损害工作记忆(一种短期记忆，能够为行为目标服务的一种短期记忆，对许多高阶认知功能的执行至关重要)所涉及的特定过程，以及苯二氮卓类药物引起的工作记忆损害与抗胆碱能药物东莨菪碱引起的工作记忆损害有质的不同。实验2和实验3将检验这样一种假设，即苯二氮卓类药物选择性地损害元记忆(人们对自己记忆的知识和意识；获得新信息和改变行为的基本先决条件)所涉及的特定过程，并且苯二氮卓类药物引起的元记忆障碍与东莨菪碱和酒精引起的元记忆障碍有本质上的不同。实验4将通过检测苯二氮卓类催眠药三唑仑的遗忘和镇静作用随不同剂量的兴奋剂d-苯丙胺和不同剂量的三唑仑给药的变化，来检验苯二氮卓类药物的记忆损害效应可以从药物的镇静作用中分离出来的假设。实验5将通过检测在重复服用苯二氮卓类药物的过程中，耐受性发展到对镇静和记忆的影响的不同程度来检验关于健忘剂和镇静作用分离的假设；结果也将为苯二氮卓类药物的长期使用者提供直接的临床相关信息。除了加强对苯二氮类药物诱导的健忘症及其神经化学特异性的理解外，这一独特地结合了药理学和认知操作的新项目的数据将有助于更好地理解人类记忆过程的特殊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，并根据长期吸毒者的具体能力量身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.