Potential serotonin 5-HT(1A) and dopamine D(4) receptor modulation of the discriminative stimulus effects of amphetamine in rats.
Potential serotonin 5-HT(1A) and dopamine D(4) receptor modulation of the discriminative stimulus effects of amphetamine in rats.
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DOI：
10.1097/fbp.0b013e328349fc31
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发表时间：
2011-09
影响因子：
1.6
通讯作者：
Nichols DE
中科院分区：
文献类型：
--
作者：
Marona-Lewicka D;Nichols DE
多巴胺能系统的激活是 (+)-安非他明行为效应的基础，并在其辨别刺激特性中起主要作用。尽管血清素受体调节大脑中的多巴胺水平，并且 5-HT1A 和 5-HT2 受体激动剂并不模仿 (+)-安非他明，但用 5-HT2A/2C 激动剂预处理可显着增强 (+)-安非他明信号。此外，5-HT2拮抗剂不会改变(+)-安非他明的辨别刺激作用，但5-HT1A拮抗剂从未在(+)-安非他明训练的大鼠中进行过测试。本研究试图表征 5-HT1A 拮抗剂 WAY 100635 对 (+)-安非他明诱导的歧视刺激效应的影响。雄性 Sprague-Dawley 大鼠接受两杠杆、固定比率 (FR) 50、食物强化任务的训练，并以 (+)-苯丙胺硫酸盐（1.0 mg/kg，腹腔注射，30 分钟预处理时间）作为辨别刺激。然后用 WAY 100635 进行替代和组合测试。 WAY 100635 并未对接受安非他明训练的大鼠产生替代作用，但显着增加了行为干扰。在组合测试中，0.4 和 5.4 mg/kg 剂量的 WAY 100635 增强了安非他明提示。我们认为低剂量的 WAY 100635 通过阻断 5-HT1A 受体来增强 (+)-安非他明信号，但高剂量的 WAY 100635 对多巴胺 D4 受体的刺激可能是增强安非他明诱导的行为敏化的原因。替代测试中行为干扰的高比例可能表明，经过训练以区分（+）-安非他明和盐水的大鼠表现出行为敏感，这种敏感无法通过药物区分测定检测到，但可能表现为多动和破坏操作行为的刻板行为。
Activation of the dopaminergic system underlies the behavioral effects of (+)-amphetamine, and plays the major role in its discriminative stimulus properties. Although serotonin receptors modulate dopamine levels in the brain, and 5-HT1A and 5-HT2 receptor agonists do not mimic (+)-amphetamine, pretreatment with 5-HT2A/2C agonists significantly potentiates the (+)-amphetamine cue. Further, 5-HT2 antagonists do not modify the discriminative stimulus effect of (+)-amphetamine, but 5-HT1A antagonists have never been tested in (+)-amphetamine-trained rats. The present study sought to characterize the effects of the 5-HT1A antagonist WAY 100635 on (+)-amphetamine-induced discriminative stimulus effects. Male Sprague-Dawley rats were trained in a two-lever, fixed ratio (FR) 50, food-reinforced task with (+)-amphetamine sulfate (1.0 mg/kg, i.p., 30 min pretreatment time) as the discriminative stimulus. Substitution and combination tests with WAY 100635 were then performed. WAY 100635 did not produce substitution in amphetamine-trained rats, but significantly increased behavioral disruption. In combination tests 0.4 and 5.4 mg/kg doses of WAY 100635 potentiated the amphetamine cue. We suggest that low doses of WAY 100635 potentiated the (+)-amphetamine cue by blockade of 5-HT1A receptors, but stimulation of the dopamine D4 receptor by higher doses of WAY 100635 may be responsible for potentiation of amphetamine-induced behavioral sensitization. The high percentage of behavioral disruption in substitution tests might suggest that rats trained to discriminate (+)-amphetamine from saline show behavioral sensitization that is not detectable by the drug discrimination assay but may be expressed as hyperactivity and stereotypic behavior that disrupts operant behavior.