Department of Psychology, Liverpool University, P.O. Box 147, Liverpool L69 3BX, UK.
J Psychopharmacol. 1994 Jan;8(4):213-21. doi: 10.1177/026988119400800404.
This study assessed the dependence potential of S-14506 [ 1- [ 2-(4-fluorobenzoylamino)ethyl]-4-(7-methoxy napthyl) piperazine], a novel, potent 5-HT(1A) full agonist with anxiolytic and antidepressant actions in animal models. The dependence potential of S-14506 was compared with that of the benzodiazepine (BZ) chlordiazepoxide (CDP). BZ withdrawal caused weight loss, aphagia and hyperthermia after chronic b.i.d. treatment for 21 days. None of these withdrawal effects were seen after similar b.i.d. S-14506 treatment at high doses. However, the acute pharmacological actions of CDP and S-14506 differed on a number of indices. Specifically, CDP increased food intake and body weight, whilst S-14506 decreased these measures, possibly due to the induction of the serotonin syndrome. Of particular interest was the observation that S-14506 induced marked hypothermia, to which complete tolerance developed very rapidly (after only 1 day). The observation of marked, rapid tolerance to S-14506-induced hypothermia, in conjunction with the absence of withdrawal hyperthermia after prolonged chronic treatment at high doses, suggests that tolerance to this effect of S-14506 can be dissociated from dependence. Collectively, the data reported suggest that the full 5-HT(1A) agonist S-14506 is devoid of dependence potential, other human and animal studies having previously suggested that partial 5-HT(1A) agonists typically induce no, or minimal, dependence.
本研究评估了 S-14506[1- [2-（4-氟苯甲酰基）氨基）乙基]-4-（7-甲氧基萘基）哌嗪]的依赖潜力，S-14506 是一种新型、有效的 5-HT（1A）完全激动剂，具有抗焦虑和抗抑郁作用，在动物模型中。S-14506 的依赖潜力与苯二氮䓬（BZ）地西泮（CDP）进行了比较。BZ 戒断在慢性 b.i.d. 治疗 21 天后导致体重减轻、厌食和体温升高。在类似的 b.i.d. S-14506 高剂量治疗后，没有观察到这些戒断效应。然而，CDP 和 S-14506 的急性药理作用在许多指标上存在差异。具体来说，CDP 增加了食物摄入量和体重，而 S-14506 降低了这些指标，这可能是由于诱导了 5-羟色胺综合征。特别值得注意的是，观察到 S-14506 引起明显的体温过低，而对这种作用的完全耐受性非常迅速地发展（仅 1 天后）。对 S-14506 诱导的体温过低的明显、快速耐受的观察，以及在高剂量长期慢性治疗后没有戒断性体温升高，表明对这种 S-14506 作用的耐受性可以与依赖性分离。总的来说，报告的数据表明，完全 5-HT（1A）激动剂 S-14506 没有依赖性潜力，而之前的其他人类和动物研究表明，部分 5-HT（1A）激动剂通常不会引起依赖性，或者只有最小的依赖性。
