Kleven M S, Koek W
Centre de Recherche Pierre Fabre, Castres, France.
J Pharmacol Exp Ther. 1998 Jan;284(1):238-49.
In this study we examined the effects of 5-HT1A ligands in rats trained to discriminate 0.16 mg/kg i.p. 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) from saline in a two-lever, fixed ratio (FR)10 schedule of food reinforcement, and in pigeons trained to discriminate 0.31 mg/kg i.m. 8-OH-DPAT from saline in a two-key, FR30 schedule of food reinforcement. In both species, 8-OH-DPAT and a variety of structurally unrelated 5-HT1A ligands occasioned dose-related, relatively high levels of drug-appropriate selection (i.e. > or = 67%). A significant positive correlation was found between estimated ED50 values in both species (r = 0.84, P < .001). Further, 5-HT1A antagonists, NAN-190, penbutolol, (-)-pindolol, tertatolol and WAY-100635, produced dose-related decreases in 8-OH-DPAT-appropriate selection, and their potencies for antagonism in rats and pigeons were highly correlated (r = 0.96, P < .01). The potency of WAY 100635 in rats and pigeons was quantified by Schild analysis (apparent in vivo pA2 values: 7.8 vs. 8.3, rat vs. pigeon respectively). Although most 5-HT1A agonists produced similar 8-OH-DPAT-like discriminative stimulus effects in both species, two compounds, lisuride and eltoprazine, occasioned high levels of drug-appropriate selection in pigeons, but not in rats. In contrast, idazoxan, yohimbine, LEK 8804 and BMY 7378 produced greater effects in rats. Among this latter group of compounds, only BMY 7378 blocked the discriminative stimulus effects of 8-OH-DPAT in pigeons, which suggested that intermediate levels of drug-appropriate selection observed with the remaining compounds are not necessarily the result of low intrinsic activity. Overall, these results demonstrate similarities in the discriminative stimulus effects of 8-OH-DPAT in rats and pigeons despite different training conditions (e.g., training dose and route of administration). Even so, the finding that some 5-HT1A ligands did not produce similar effects in rats and pigeons illustrates the need to examine possible 8-OH-DPAT-like discriminative stimulus effects of compounds in both species.
在本研究中，我们检测了5-HT1A配体对大鼠和鸽子辨别行为的影响。大鼠经训练后，在两杆固定比率（FR）10的食物强化程序中，区分腹腔注射0.16mg/kg的8-羟基-2-（二正丙基氨基）四氢萘（8-OH-DPAT）和生理盐水；鸽子经训练后，在两键FR30的食物强化程序中，区分肌肉注射0.31mg/kg的8-OH-DPAT和生理盐水。在这两个物种中，8-OH-DPAT和多种结构不相关的5-HT1A配体均引起与剂量相关的、相对较高水平的药物适应性选择（即≥67%）。两个物种的估计ED50值之间存在显著正相关（r = 0.84，P <.001）。此外，5-HT1A拮抗剂NAN-190、喷布洛尔、（-）-吲哚洛尔、替他洛尔和WAY-100635，使8-OH-DPAT适应性选择呈剂量依赖性降低，它们在大鼠和鸽子中的拮抗效力高度相关（r = 0.96，P <.01）。通过Schild分析对WAY 100635在大鼠和鸽子中的效力进行了量化（体内表观pA2值：大鼠为7.8，鸽子为8.3）。尽管大多数5-HT1A激动剂在两个物种中产生相似的8-OH-DPAT样辨别刺激效应，但利苏瑞得和依他普仑这两种化合物在鸽子中引起高水平的药物适应性选择，而在大鼠中则不然。相反，咪唑克生、育亨宾、LEK 8804和BMY 7378在大鼠中产生更大的效应。在这后一组化合物中，只有BMY 7378阻断了鸽子中8-OH-DPAT的辨别刺激效应，这表明其余化合物观察到的中等水平的药物适应性选择不一定是低内在活性的结果。总体而言，这些结果表明，尽管训练条件不同（如训练剂量和给药途径），8-OH-DPAT在大鼠和鸽子中的辨别刺激效应仍具有相似性。即便如此，一些5-HT1A配体在大鼠和鸽子中未产生相似效应这一发现表明，有必要在两个物种中检测化合物可能的8-OH-DPAT样辨别刺激效应。
