Qiu Yanyan, Zhang Yanan, Li Jun-Xu
Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA.
Research Triangle Institute, Research Triangle Park, NC, USA.
Eur J Pharmacol. 2015 Feb 15;749:133-41. doi: 10.1016/j.ejphar.2015.01.013. Epub 2015 Jan 21.
Although imidazoline I2 receptor ligands have been used as discriminative stimuli, the role of efficacy of I2 receptor ligands as a critical determinant in drug discrimination has not been explored. This study characterized the discriminative stimulus effects of selective imidazoline I2 receptor ligands BU224 (a low-efficacy I2 receptor ligand) and phenyzoline (a higher efficacy I2 receptor ligand) in rats. Two groups of male Sprague-Dawley rats were trained to discriminate 5.6mg/kg BU224 or 32mg/kg phenyzoline (i.p.) from their vehicle in a two-lever food-reinforced drug discrimination procedure, respectively. All rats acquired the discriminations after an average of 18 (BU224) and 56 (phenyzoline) training sessions, respectively. BU224 and phenyzoline completely substituted for one another symmetrically. Several I2 receptor ligands (tracizoline, CR4056, RS45041, and idazoxan) all occasioned>80% drug-associated lever responding in both discriminations. The I2 receptor ligand 2-BFI and a monoamine oxidase inhibitor harmane occasioned>80% drug-associated lever responding in rats discriminating BU224. Other drugs that occasioned partial or less substitution to BU224 cue included clonidine, methamphetamine, ketamine, morphine, methadone and agmatine. Clonidine, methamphetamine and morphine also only produced partial substitution to phenyzoline cue. Naltrexone, dopamine D2 receptor antagonist haloperidol and serotonin (5-HT)2A receptor antagonist MDL100907 failed to alter the discriminative stimulus effects of BU224 or phenyzoline. Combined, these results are the first to demonstrate that BU224 and phenyzoline can serve as discriminative stimuli and that the low-efficacy I2 receptor ligand BU224 shares similar discriminative stimulus effects with higher-efficacy I2 receptor ligands such as phenyzoline and 2-BFI.
尽管咪唑啉I2受体配体已被用作辨别刺激物，但I2受体配体的效能作为药物辨别中关键决定因素的作用尚未得到探索。本研究表征了选择性咪唑啉I2受体配体BU224（一种低效I2受体配体）和苯乙唑啉（一种高效I2受体配体）在大鼠中的辨别刺激效应。两组雄性Sprague-Dawley大鼠分别在双杠杆食物强化药物辨别程序中接受训练，以区分5.6mg/kg的BU224或32mg/kg的苯乙唑啉（腹腔注射）与其溶剂。所有大鼠分别在平均18次（BU224）和56次（苯乙唑啉）训练后获得辨别能力。BU224和苯乙唑啉完全对称地相互替代。几种I2受体配体（曲唑啉、CR4056、RS45041和咪唑克生）在两种辨别中均引起>80%的药物相关杠杆反应。I2受体配体2-BFI和单胺氧化酶抑制剂哈尔满在辨别BU224的大鼠中引起>80%的药物相关杠杆反应。其他对BU224线索产生部分或较少替代的药物包括可乐定、甲基苯丙胺、氯胺酮、吗啡、美沙酮和胍丁胺。可乐定、甲基苯丙胺和吗啡对苯乙唑啉线索也仅产生部分替代。纳曲酮、多巴胺D2受体拮抗剂氟哌啶醇和5-羟色胺（5-HT）2A受体拮抗剂MDL100907未能改变BU224或苯乙唑啉的辨别刺激效应。综合来看，这些结果首次证明BU224和苯乙唑啉可作为辨别刺激物，并且低效I2受体配体BU224与高效I2受体配体如苯乙唑啉和2-BFI具有相似的辨别刺激效应。
