Griebel G, Perrault G, Sanger D J
Synthélabo Recherche, Bagneux, France.
Behav Pharmacol. 1997 Nov;8(6-7):549-60. doi: 10.1097/00008877-199711000-00013.
The present experiments compared the behavioural effects of one cholecystokininA (CCKA; lorglumide) and two CCKB (PD 135,158 and LY 288513) receptor antagonists in classical animal models of anxiety, including conflict tests (punished lever pressing and Vogel drinking tests in rats) and exploratory models (elevated plus-maze test in rats and light/dark choice test in mice), and a recently developed mouse defence test battery (MDTB) which has been validated for the screening of both anti-panic and classical anxiolytic (i.e. benzodiazepines) drugs. Diazepam was used as a positive control. Results showed that all three CCK receptor antagonists were inactive in both conflict tests. Furthermore, despite the incorporation of more ethologically-derived measures (i.e. risk assessment activities or directed exploration, or both) no effects were observed in the elevated plus-maze and in the light/dark tests. These profiles contrast with that of diazepam which displayed clear anxiolytic-like effects in these models. In the MDTB, the CCK receptor antagonists failed to modify parameters (i.e. risk assessment, defensive threat/attack and escape attempts), which have been shown to be particularly sensitive to drugs effective in the treatment of generalized anxiety. By contrast, the CCKB receptor antagnoists PD 135,158 (0.001-0.01, 1 mg/kg, i.p.) and LY 288513 (1 and 3 mg/kg, i.p.) significantly decreased avoidance distance when the rat was first placed in the test apparatus, an effect which is consistent with an anti-panic-like action. Overall, these findings support the idea that classical animal models of anxiety may not be suitable for evaluation of the behavioural effects of CCK receptor antagonists, whereas tests which may model certain aspects of human panic such as the MDTB appear to be more reliable tools when screening such compounds.
本实验比较了一种胆囊收缩素A（CCKA；洛谷胺）和两种CCKB（PD 135158和LY 288513）受体拮抗剂在经典动物焦虑模型中的行为效应，这些模型包括冲突试验（大鼠的惩罚性杠杆按压和沃格尔饮水试验）和探索性模型（大鼠的高架十字迷宫试验和小鼠的明暗选择试验），以及最近开发的已被验证可用于筛选抗惊恐和经典抗焦虑（即苯二氮䓬类）药物的小鼠防御试验组（MDTB）。地西泮用作阳性对照。结果表明，所有三种CCK受体拮抗剂在两种冲突试验中均无活性。此外，尽管纳入了更多源自行为学的指标（即风险评估活动或定向探索，或两者兼有），但在高架十字迷宫试验和明暗试验中均未观察到任何效应。这些结果与地西泮的情况形成对比，地西泮在这些模型中表现出明显的抗焦虑样效应。在MDTB中，CCK受体拮抗剂未能改变已证明对有效治疗广泛性焦虑的药物特别敏感的参数（即风险评估、防御性威胁/攻击和逃避企图）。相比之下，CCKB受体拮抗剂PD 135158（0.001 - 0.01、1 mg/kg，腹腔注射）和LY 288513（1和3 mg/kg，腹腔注射）在大鼠首次放入试验装置时显著缩短了回避距离，这一效应与抗惊恐样作用一致。总体而言，这些发现支持这样一种观点，即经典的动物焦虑模型可能不适用于评估CCK受体拮抗剂的行为效应，而在筛选此类化合物时，可能模拟人类惊恐某些方面的试验，如MDTB，似乎是更可靠的工具。
