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MAUDSLEY RATS, BENZODIAZEPINES AND CONFLICT BEHAVIOR

莫兹利大鼠、苯二氮卓类药物和冲突行为

基本信息

批准号：
3381647
负责人：
RANDALL L COMMISSARIS
金额：
$ 6.37万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1987
资助国家：
美国
起止时间：
1987-04-01 至 1989-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3381647
关键词：
barbiturates benzodiazepines clinical anxiety diazepam drug receptors ethology genetic strain laboratory rat psychopharmacology

项目摘要

The Maudsley rat strains may be one of the best-kept secrets in Biological Psychiatry. Selectively bred by Broadhurst in the 1950s and 1960s for their high and low levels of emotionality (Open Field Defecation; OFD), the Maudsley Reactive and Non-Reactive rats represent a genetically-based "animal model" for the study of anxiety disorders. Surprisingly, reports on the behavioral pharmacology of these Maudsley rats do not exist. This is perhaps because of two problems associated with OFD testing: (1) it does not lend itself to repeated measures designs and (2) "floor effects" (i.e., zero defecation in the Non-Reactive rats), which make drug manipulations difficult to interpret. Using two of the three strains of Maudsley rats which Dr. Gordon Harrington at the University of North Iowa has been breeding, we have shown that Non-Reactive (MNRA/Har) rats differ from Reactive (MR/Har) rats in their basal performance in the Conditional Suppression of Drinking (CSD) paradigm, with the MNRA/Har rats accepting more shocks than MR/Har rats. This CSD procedure, related to the Vogel and Geller-Seifter procedures, has been used extensively in the study of "anxiety" and anti-anxiety agents. The first objective of the present studies is to determine the basal CSD performance of Harrington's second Non-Reactive strain (MNR/Har). These results will shed light on the relationship between OFD and CSD behavior. Finally, because the CSD procedure is a non-zero baseline procedure employing repeated measures, a series of behavioral pharmacology studies will be conducted. Specifically, the effects of benzodiazepine agonists, the benzodiazepine antagonist Ro15-1788, benzodiazepine "inverse agonists" (FG-7142 and CGS-8216), and barbiturates will be determined in these three Maudsley rat strains. Based on the greater number of benzodiazepine receptors in the Non-Reactive rats compared to the Reactive rats, the Non-Reactive rats should show a greater response to both the benzodiazepine agonists and inverse agonists. Preliminary data with a single dose of diazepam (5 mg/kg) suggest that this may be the case. The barbiturates represent "controls", with no strain differences expected to occur. The results of these studies will greatly enhance our understanding of the behavior and pharmacology of these Maudsley rat strains, and will open up areas for additional basic and clinical investigations into the nature of anxiety disorders and emotional behavior.

莫兹利鼠的品系可能是世界上保守得最好的秘密之一，生物精神病学布罗德赫斯特在20世纪50年代精心培育和20世纪60年代的高水平和低水平的情感（开放现场排便; OFD），毛兹利反应和非反应大鼠代表了一种基于遗传学的“动物模型”，用于研究焦虑症令人惊讶的是，这些莫兹利大鼠的药理学是不存在的。这也许是由于与OFD测试相关的两个问题：（1）它确实不适合重复措施设计和（2）“地板效应” (i.e.,无反应大鼠中的零排便），其使药物难以解释的操纵。使用三个中的两个戈登哈灵顿博士在北爱荷华州大学一直在培育，我们已经表明，非反应性（MNRA/Har）大鼠与反应性（MR/Har）大鼠不同大鼠在条件性抑制中的基础表现饮水（CSD）模式，MNRA/Har大鼠接受比MR/Har大鼠更多的电击。 CSD的这一程序，涉及到 Vogel和Geller-Seifter程序广泛研究“焦虑”和抗焦虑剂。的本研究的第一个目标是确定基础哈灵顿第二非反应菌株的CSD性能 (MNR/Har）。这些结果将有助于阐明 OFD和CSD行为之间的关系最后，因为CSD 程序是一个非零基线程序，措施，一系列的行为药理学研究将进行。具体来说，苯二氮卓类激动剂的作用，苯二氮卓类拮抗剂Ro 15 -1788， “反向激动剂”（FG-7142和CGS-8216）和巴比妥类药物将在这三种莫兹利大鼠品系中可以确定。基于非反应性细胞中苯二氮卓类受体数量更多与反应性大鼠相比，非反应性大鼠应对苯二氮卓类激动剂和反向激动剂地西泮单次给药的初步数据（5 mg/kg）表明情况可能如此。巴比妥类代表“对照”，预计不会出现菌株差异。这些研究的结果将大大提高我们的了解这些药物的行为和药理学，莫兹利老鼠品系，并将开辟地区，为额外的基本和临床调查的性质焦虑症，情绪行为