Evenden J L
Preclinical Research Department, Astra Arcus AB, Södertälje, Sweden.
Psychopharmacology (Berl). 1992;109(1-2):134-44. doi: 10.1007/BF02245491.
8-OH-DPAT, a selective 5-HT1A agonist, has variously been found to impair, have no effect on or enhance the conditioned avoidance response (CAR). Procedural differences may account for the difference in results. In the first experiment in the present study rats were trained in the two-way active avoidance procedure to a criterion of 65% avoidance. Separate groups of rats were treated with 0.01, 0.1 or 1.0 mg/kg 8-OH-DPAT SC once per day for 14 days. The rats were tested in the CAR each day 5 min after treatment, using a 10 s light and tone conditioned stimulus and five 0.2 mA/0.5 s electric shocks. On the first day the doses of 0.1 and 1.0 mg/kg impaired avoidance, but by the end of training these two doses increased avoidance. This change in effect was accompanied by a 15-fold increase in the number of trials in which the subject crossed during a 10 s period of the ITI, which in turn led to a significant impairment in the discrimination ratio. The results of this experiment show that with repeated treatment 8-OH-DPAT changes from being antipsychotic like to being stimulant-like. The latter effect produces an improvement in avoidance, probably due to a non-specific increase in activity. In the second experiment, the rats were divided into groups based upon the undrugged performance. The avoidance-enhancing effect of 8-OH-DPAT was greater in magnitude in a group of poor performers, but was qualitatively similar in good performers. In the second stage of the experiment, gradual withdrawal from the drug was compared with sudden withdrawal. In the gradual withdrawal group, a reduction in the dose from 0.085 mg/kg to 0.01 mg/kg resulted in a gradual disappearance of the enhanced activity. There was an almost linear relationship between performance and the log dose of the drug, suggesting that the increase in activity seen after repeated administration of 8-OH-DPAT is directly related to the acute level of drug administered. This effect was evident in both good and poor performers. On the basis of these results it is suggested that many, but not all, antidepressant-like effects of 8-OH-DPAT may result from changes in activity.
8-羟基二丙基氨基四氢萘（8-OH-DPAT）是一种选择性5-羟色胺1A（5-HT1A）激动剂，人们发现它对条件性回避反应（CAR）有不同影响，包括损害、无影响或增强该反应。实验程序的差异可能是导致结果不同的原因。在本研究的第一个实验中，大鼠接受双向主动回避训练，达到65%回避率的标准。将大鼠分成不同组，每天皮下注射一次0.01、0.1或1.0毫克/千克的8-OH-DPAT，持续14天。每天在给药后5分钟对大鼠进行CAR测试，使用10秒的光和声条件刺激以及五次0.2毫安/0.5秒的电击。第一天，0.1和1.0毫克/千克的剂量损害了回避反应，但到训练结束时，这两个剂量增加了回避反应。这种效果变化伴随着在ITI的10秒期间内受试大鼠穿越次数增加了15倍，这反过来又导致辨别率显著受损。该实验结果表明，随着重复给药，8-OH-DPAT的作用从类似抗精神病药物转变为类似兴奋剂。后一种效果导致回避反应改善，可能是由于活动的非特异性增加。在第二个实验中，根据未用药时的表现将大鼠分组。8-OH-DPAT的回避增强作用在表现较差的一组中幅度更大，但在表现较好的组中性质相似。在实验的第二阶段，比较了药物的逐渐撤药和突然撤药。在逐渐撤药组中，剂量从0.085毫克/千克降至0.01毫克/千克导致增强的活动逐渐消失。表现与药物对数剂量之间几乎呈线性关系，这表明重复给予8-OH-DPAT后观察到的活动增加与给药的急性剂量直接相关。这种效果在表现好和表现差的大鼠中都很明显。基于这些结果，有人提出8-OH-DPAT的许多（但不是全部）类抗抑郁作用可能是由活动变化引起的。
