WAY 100635 produces discriminative stimulus effects in rats mediated by dopamine D4 receptor activation
WAY 100635 produces discriminative stimulus effects in rats mediated by dopamine D4 receptor activation
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DOI：
10.1097/fbp.0b013e3283242f1a
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发表时间：
2009-02-01
影响因子：
1.6
通讯作者：
Nichols, David E.
中科院分区：
文献类型：
--
作者：
Marona-Lewicka, Danuta;Nichols, David E.
体外研究表明，WAY 100635不仅是一种有效的5-HT 1A拮抗剂，而且对多巴胺D-4受体具有高亲和力和功效。然而，尚未研究该化合物的行为效应。本研究旨在表征WAY 100635产生的辨别性刺激效应。雄性Sprague-Dawley大鼠在两个杠杆，固定比例50，食物强化任务与WAY 100635（10 μ mol/kg）作为区别性刺激。用不同剂量的WAY 100635和（-）-吲哚洛尔进行替代试验，并用两种5-HT 1A激动剂8-OH-DPAT和LY 293284以及两种多巴胺D4拮抗剂索奈哌唑和A-381393进行联合试验。用低剂量（0.74 μ mol/kg）WAY 100635训练的大鼠在超过3个月的训练后不能学习辨别任务。训练区分10 μ mol/kg WAY 100635和生理盐水的大鼠在大约35次训练后达到了准确性标准。WAY 100635（2.5-10 μ mol/kg）引起WAY 100635-适当应答的剂量依赖性增加，平均有效剂量为3.44 μ mol/kg，而生理盐水或吲哚洛尔（5-25 μ mol/kg）给药导致0%药物水平应答。用5-HT 1A激动剂8-OH-DPAT或LY 293284预处理没有改变WAY 100635曲线，但用选择性多巴胺D-4拮抗剂sonepiprazole或A-381393预处理完全阻断了该线索。这些结果表明WAY 100635产生的区别性刺激效应是由多巴胺D-4受体的激活介导的。行为药理学20：114-118（C）2009年威科健康垂直酒吧Lippincott威廉姆斯&威尔金斯。
In-vitro studies have shown that WAY 100635 is not only a potent 5-HT1A antagonist, but also has high affinity and efficacy at the dopamine D-4 receptor. Nevertheless, the behavioral effects of this compound have not been investigated. This study sought to characterize the discriminative stimulus effects produced by WAY 100635. Male Sprague-Dawley rats were trained in a two-lever, fixed ratio 50, food-reinforced task with WAY 100635 (10 mu mol/kg) as a discriminative stimulus. Substitution tests with different doses of WAY 100635 and (-)-pindolol, and combination tests with two 5-HT1A agonists, 8-OH-DPAT and LY 293284; and two dopamine D4 antagonists, sonepiprazole and A-381393, were performed. Rats trained with a low dose (0.74 mu mol/kg) of WAY 100635 could not learn the discrimination task after more than 3 months of sessions. Rats trained to discriminate 10 mu mol/kg of WAY 100635 from saline achieved the criterion of accuracy after approximately 35 training sessions. WAY 100635 (2.5-10 mu mol/kg) produced a dose-dependent increase in WAY 100635-appropriate responding, with a mean effective dose of 3.44 mu mol/kg, whereas saline or pindolol (5-25 mu mol/kg) administration resulted in 0% drug lever responding. Pretreatment with the 5-HT1A agonists 8-OH-DPAT or LY 293284 did not modify the WAY 100635 curve, but pretreatment with the selective dopamine D-4 antagonists sonepiprazole or A-381393 completely blocked the cue. These results indicate that the discriminative stimulus effect produced by WAY 100635 is mediated by activation of dopamine D-4 receptors. Behavioural Pharmacology 20:114-118 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.