Tricklebank M D, Neill J, Kidd E J, Fozard J R
Eur J Pharmacol. 1987 Jan 6;133(1):47-56. doi: 10.1016/0014-2999(87)90204-4.
Male Sprague-Dawley rats were trained to discriminate the putative 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) from saline in a 2-lever operant drug discrimination paradigm. The 8-OH-DPAT cue was found to be highly selective; neither the 5-HT receptor agonists, quipazine, LSD, MK 212 and RU 24969, the 5-HT releasing agent, p-chloroamphetamine, nor the alpha 2-adrenoceptor agonist, clonidine, were able to substitute for 8-OH-DPAT in tests of generalization. In contrast, both buspirone and TVX Q 7821, which like 8-OH-DPAT have high affinity and selectivity for the 5-HT1A recognition site, generalized to the 8-OH-DPAT cue in a dose-dependent manner. The discriminative stimulus properties of 8-OH-DPAT were not antagonized by the 5-HT2 receptor antagonist, ketanserin, or the selective beta 1- and beta 2-adrenoceptor antagonists, betaxolol and ICI 118.551, indicating that neither 5-HT2 receptors, nor beta-adrenoceptors play a significant role in the behaviour. However, the 8-OH-DPAT cue was antagonized stereoselectively by pindolol and alprenolol, which have relatively high affinity and stereoselectivity for 5-HT1, but not 5-HT2, recognition sites. Similarly, the capacity of TVX Q 7821 to generalize to the 8-OH-DPAT cue could be blocked by pindolol. In view of the fact that 8-OH-DPAT has negligible affinity for the 5-HT1B site, the above results are consistent with its discriminative stimulus properties being mediated by the putative 5-HT1A receptor. Moreover, agonist activity at central 5-HT1A receptors may be an important mechanism contributing to the anxiolytic properties of buspirone and TVX Q 7821.
在双杠杆操作性药物辨别范式中，训练雄性斯普拉格-道利大鼠从盐水中辨别假定的5-羟色胺1A（5-HT1A）受体激动剂8-羟基-2-（二正丙基氨基）四氢萘（8-OH-DPAT）。发现8-OH-DPAT线索具有高度选择性；5-羟色胺受体激动剂喹哌嗪、麦角酸二乙胺、MK 212和RU 24969、5-羟色胺释放剂对氯苯丙胺以及α2-肾上腺素能受体激动剂可乐定，在泛化测试中均不能替代8-OH-DPAT。相反，丁螺环酮和TVX Q 7821与8-OH-DPAT一样，对5-HT1A识别位点具有高亲和力和选择性，它们以剂量依赖的方式泛化到8-OH-DPAT线索。8-OH-DPAT的辨别刺激特性不受5-羟色胺2（5-HT2）受体拮抗剂酮色林或选择性β1和β2肾上腺素能受体拮抗剂倍他洛尔和ICI 118.551的拮抗，这表明5-HT2受体和β-肾上腺素能受体在该行为中均不发挥重要作用。然而，8-OH-DPAT线索被吲哚洛尔和阿普洛尔立体选择性拮抗，它们对5-HT1而非5-HT2识别位点具有相对较高的亲和力和立体选择性。同样，吲哚洛尔可阻断TVX Q 7821泛化到8-OH-DPAT线索的能力。鉴于8-OH-DPAT对5-HT1B位点的亲和力可忽略不计，上述结果与其辨别刺激特性由假定的5-HT1A受体介导一致。此外，中枢5-HT1A受体的激动剂活性可能是丁螺环酮和TVX Q 7821抗焦虑特性的重要作用机制。
