Ensler K, Ryan C N, Evenden J L
Department of Behavioural Pharmacology, Astra Arcus, Södertälje, Sweden.
Psychopharmacology (Berl). 1993;112(1):45-54. doi: 10.1007/BF02247362.
The behavioural effects of the serotonin 1A receptor (5-HT1A) agonist anxiolytics are generally examined after acute administration. The present study examined the effects of these substances during repeated treatment in the two-way active avoidance (Conditioned Avoidance Response, CAR) procedure. Previously it has been found that the prototypical 5-HT1A receptor agonist, 8-OH-DPAT, increases avoidance, apparently by increasing general activity, after repeated administration but not on acute administration. In the present study, it was demonstrated that this increase in activity can be blocked by the 5-HT1A receptor antagonists (-)alprenolol (also beta adrenergic antagonist) and (S)-UH-301, but not by the non-selective 5-HT antagonist metergoline. The relatively full 5-HT1A agonist, flesinoxan, and the partial 5-HT1A agonist, ipsapirone, had qualitatively similar effects to 8-OH-DPAT, although the effect of ipsapirone was clearly smaller in magnitude. Buspirone, the 5-HT1A partial agonist/dopamine D2 antagonist, markedly decreased activity, and thus avoidance of the shocks, in a manner similar to the antipsychotic drug, haloperidol. However, when the hypothermic effects of these compounds were investigated after acute administration, buspirone induced a strong hypothermic response in rats, like 8-OH-DPAT, whereas haloperidol had no effect. With the exception of buspirone, the effectiveness of these compounds in increasing activity in the CAR test appears to be related to their agonist efficacy at the 5-HT1A receptor. Similarities between the effects of these compounds and previously reported results with serotonin-depleting agents (Tenen 1967; Breese et al. 1974) suggest that the net effect of 5-HT1A agonists after repeated administration is to produce a functional reduction in 5-HT activity. The activity suppressing action of buspirone indicates that the dopamine antagonist activity of buspirone predominates in this procedure.
5-羟色胺1A受体（5-HT1A）激动剂类抗焦虑药的行为效应通常是在急性给药后进行研究的。本研究在双向主动回避（条件性回避反应，CAR）实验中，考察了这些物质在重复给药过程中的效应。此前已经发现，典型的5-HT1A受体激动剂8-OH-DPAT在重复给药后而非急性给药后，明显通过增加一般活动来提高回避率。在本研究中，已证明这种活动增加可被5-HT1A受体拮抗剂（-）阿普洛尔（也是β肾上腺素能拮抗剂）和（S）-UH-301阻断，但不能被非选择性5-HT拮抗剂美替拉酮阻断。相对完全的5-HT1A激动剂氟辛克生和部分5-HT1A激动剂伊沙匹隆，在性质上与8-OH-DPAT有相似的效应，尽管伊沙匹隆的效应在程度上明显较小。5-HT1A部分激动剂/多巴胺D2拮抗剂丁螺环酮，以类似于抗精神病药物氟哌啶醇的方式，显著降低活动，从而减少对电击的回避。然而当在急性给药后研究这些化合物的体温过低效应时，丁螺环酮像8-OH-DPAT一样在大鼠中诱导出强烈的体温过低反应，而氟哌啶醇则无作用。除丁螺环酮外，这些化合物在CAR实验中提高活动的有效性似乎与其在5-HT1A受体上的激动剂效力有关。这些化合物的效应与先前报道的5-羟色胺耗竭剂的结果（Tenen于1967年；Breese等人于1974年）之间的相似性表明，5-HT1A激动剂在重复给药后的净效应是导致5-羟色胺活性的功能性降低。丁螺环酮的活动抑制作用表明，丁螺环酮的多巴胺拮抗剂活性在此过程中占主导地位。
