Gleason S D, Leander J D
The Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Behav Pharmacol. 1999 Dec;10(8):785-91. doi: 10.1097/00008877-199912000-00010.
Since the introduction of buspirone, the 5-HT1A receptor has been a focal point for serotonergic research into the treatment of anxiety. Two of the more commonly used methodologies for evaluating potential anxiolytics are the Geller-Seifter model and the elevated plus maze. In the Geller-Seifter model, administration of 5-HT1A agonists produce an anxiolytic-like profile consisting of an increase in the number of responses made during the punished component. An anxiolytic-like response in the elevated plus maze consists of an increase in the number of entries and/or time spent in the open arms of the maze. Recently, there have been reports of differential drug effects with 5-HT1A ligands in the elevated plus maze depending on when in the diurnal cycle the 5-HT1A agents were administered. The purpose of the current study was to characterize the response to 5-HT1A compounds in normal and reverse light cycle animals in the Geller-Seifter model. 8-OH-DPAT [(+/-)-2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronapthalene] produced a decrease in unpunished responding and an increase in punished responding during both the light and dark phase. The administration of WAY 100,635 [N-¿2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl¿-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloridel alone was without effect in both the light and dark phase. Furthermore, pre-treatment with WAY 100,635 completely antagonized both the rate-decreasing effects in the unpunished component and the increase in punished responding observed with 8-OH-DPAT during both the light and dark phase. The results of the current study diverge from previous findings of sensitivity to the diurnal cycle in other models reflective of modulation of the 5-HT1A receptor. The robustness of the response, in this case punished lever pressing, may be less sensitive than other more naturalistic or ethological methods (i.e. elevated plus maze) in detecting the subtle changes in receptor function due to the diurnal cycle.
自从丁螺环酮被引入以来，5-羟色胺1A（5-HT1A）受体一直是血清素能研究治疗焦虑症的焦点。评估潜在抗焦虑药的两种更常用方法是盖勒-西弗特模型（Geller-Seifter model）和高架十字迷宫（elevated plus maze）。在盖勒-西弗特模型中，给予5-HT1A激动剂会产生一种抗焦虑样反应，其表现为在受惩罚部分的反应次数增加。在高架十字迷宫中的抗焦虑样反应包括进入迷宫开放臂的次数增加和/或在开放臂中花费的时间增加。最近，有报道称，在高架十字迷宫中，根据5-HT1A药物在昼夜周期中的给药时间不同，5-HT1A配体的药物作用存在差异。本研究的目的是在盖勒-西弗特模型中，描述正常和反光照周期动物对5-HT1A化合物的反应。8-羟基二丙胺四氢萘（8-OH-DPAT，[(+/-)-2-二丙基氨基-8-羟基-1,2,3,4-四氢萘]）在光照期和黑暗期均使无惩罚反应减少，惩罚反应增加。单独给予WAY 100,635 [N-（2-[4-（2-甲氧基苯基）-1-哌嗪基]乙基）-N-（2-吡啶基）环己烷甲酰胺三盐酸盐]在光照期和黑暗期均无作用。此外，用WAY 100,635预处理完全拮抗了无惩罚部分的速率降低效应以及在光照期和黑暗期观察到的8-OH-DPAT引起的惩罚反应增加。本研究结果与先前在反映5-HT1A受体调节的其他模型中对昼夜周期敏感性的研究结果不同。在这种情况下，即受惩罚的杠杆按压，反应的稳健性在检测由于昼夜周期导致的受体功能细微变化时，可能不如其他更自然主义或行为学方法（即高架十字迷宫）敏感。
