BEHAVIORAL PHARMACOLOGY OF CHRONIC BENZODIAZEPINE USE

长期使用苯二氮卓类药物的行为药理学

• 批准号: 3211483
• 负责人: STEPHEN Cletius FOWLER
• 金额: $ 11.72万
• 依托单位: UNIVERSITY OF MISSISSIPPI
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-04-01 至 1994-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3211483
• 关键词: albino rat; alprazolam; behavior modification; behavior test; benzodiazepines; buspirone; diazepam; drug abuse; drug administration rate /duration; drug adverse effect; drug tolerance; drug withdrawal; lorazepam; midazolam; operant conditionings; pharmacokinetics; psychological reinforcement; psychopharmacology; tranquilizer

The role of behavioral-environmental factors in the development of tolerance and drug withdrawal to benzodiazepines (BZs) will be investigated in six separate experiments with albino rats. An examination of both contingent and non-contingent components of operant responding are emphasized as potential modes for behavioral change during the development of tolerance and withdrawal. Two operant experiments will explore the development of tolerance and withdrawal produced by 30 days of pre and postsession exposure to modest doses of two BZs, midazolam (MZ) and diazepam (DZ), when reinforcement is dependent on the duration of the responses or the force of responses rather than rate of responding. Since duration of drug action is an important predictor of drug abuse and of behavioral tolerance phenomena, one experiment will compare the development of tolerance as assessed with the multiple FR:FI operant schedule to two intermediate-duration-of-action BZs, alprazolam (AP) and lorazepam (LP), which have dissimilar pharmacological profiles. AP is more efficacious clinically as an anxiolytic and LP is more efficacious as a muscle relaxant. The importance of duration of BZ activity in the development of behavioral tolerance and drug withdrawal will be further explored by manipulation of inter-drug interval in rats exposed to MZ (28 total drug exposures) as a model for drug "binging". With total cumulative dose being held constant, three different dosing regimens will be examined: continuous daily exposure, two days of exposure followed by five days of no exposure, and four days of exposure followed by three days of no exposure. Previous data on repetitive exposure to BZs will be extended to examine the importance of behavioral-environmental factors in repetitive exposure to two non-BZ anxiolytics, buspirone (BU) and gepirone (GP), which mediate their effects via 5-HT1A receptors. The final project will evaluate the importance of chronically experiencing MZ while responding in predicting long term alterations in sensitivity to BZs and the non-BZ anxiolytic buspirone (BU).

行为-环境因素在发展中的作用 将调查对苯二氮卓类药物（BZ）的耐受性和停药情况 在六个不同的白化病大鼠实验中。 对两者的检查 操作性反应的偶然和非偶然成分是 强调在发展过程中作为行为变化的潜在模式 宽容和退缩。 两个操作性实验将探讨 30天的预处理和 治疗后暴露于中等剂量的两种BZ，咪达唑仑（MZ）和 地西泮（DZ），当强化依赖于持续时间时， 反应或反应的力量，而不是反应的速度。 以来 药物作用的持续时间是药物滥用的重要预测因素， 行为耐受现象，一个实验将比较发展 耐受性的评估与多FR：FI操作时间表，以两个 中等作用持续时间的BZ，阿普唑仑（AP）和劳拉西泮（LP）， 它们具有不同的药理学特性。 AP更有效 临床上作为抗焦虑药，LP作为肌肉注射剂更有效 松弛剂 BZ活动持续时间在发展中的重要性 行为耐受性和药物戒断将进一步探讨， 在暴露于MZ的大鼠中操纵药物间间隔（28种药物 暴露）作为药物“狂欢”的模型。 总累积剂量为 保持不变，将检查三种不同的给药方案： 连续每天接触，两天接触，然后五天不接触 暴露4天，然后3天不暴露。 先前关于重复暴露于BZ的数据将被扩展到检查 行为环境因素在重复暴露中的重要性 两种非BZ抗焦虑药，丁螺环酮（BU）和吉哌隆（GP），其介导 通过5-HT 1A受体发挥作用。 最后的项目将评估 长期经历MZ的重要性，同时在预测中做出反应 对BZ和非BZ抗焦虑药敏感性的长期改变 丁螺环酮（BU）。