Goutier Wouter, Kloeze Margreet B, McCreary Andrew C
Abbott Healthcare Products B.V., C.J. van Houtenlaan 36, 1381 CP, Weesp, The Netherlands.
Addict Biol. 2015 Mar;20(2):248-58. doi: 10.1111/adb.12108. Epub 2013 Nov 20.
The present study focused on the evaluation of behavioral sensitization and cross-sensitization induced by nicotine and varenicline in rats. Furthermore, it examined the influence of varenicline, a partial alpha4beta2 nicotinic receptor agonist, on nicotine-induced sensitization. To assess the development of behavioral sensitization, rats were chronically treated with vehicle, varenicline (0.03-3.0 mg/kg), nicotine (0.4 mg/kg) or combinations for 5 days and locomotor activity was measured. The expression of sensitization was assessed following a withdrawal period (17-26 days). The present results confirmed previous data showing the development and expression of nicotine-induced sensitization of locomotor activity in the rat. Varenicline did not induce sensitization on its own. When varenicline and nicotine were repeatedly administered sequentially, varenicline blocked the development and expression of nicotine-induced sensitization. Acute varenicline blocked the expression of nicotine-induced sensitization in a dose-dependent manner. Acute varenicline did not significantly increase locomotor activity, nor did it attenuate nicotine-induced sensitization. However, varenicline did cross-sensitize to the effects of nicotine, and vice versa. The present study showed that varenicline produced a dose-dependent bidirectional cross-sensitization with nicotine. Taken together, these findings provide pre-clinical evidence that varenicline is able to attenuate the effects of nicotine, yet simultaneously 'substitutes' for the effects of nicotine in the rat. Longitudinal studies would be needed to see if similar effects are seen in the clinical setting, and whether such effects contribute to the actions of varenicline as a smoking cessation aid.
本研究聚焦于评估尼古丁和伐尼克兰在大鼠中诱导的行为敏化和交叉敏化。此外，还研究了部分α4β2烟碱受体激动剂伐尼克兰对尼古丁诱导的敏化作用的影响。为了评估行为敏化的发展，大鼠连续5天接受赋形剂、伐尼克兰（0.03 - 3.0毫克/千克）、尼古丁（0.4毫克/千克）或它们的组合治疗，并测量运动活性。在停药期（17 - 26天）后评估敏化的表达。目前的结果证实了先前的数据，即大鼠中尼古丁诱导的运动活性敏化的发展和表达。伐尼克兰自身不会诱导敏化。当伐尼克兰和尼古丁依次重复给药时，伐尼克兰会阻断尼古丁诱导的敏化的发展和表达。急性给予伐尼克兰以剂量依赖的方式阻断尼古丁诱导的敏化的表达。急性给予伐尼克兰不会显著增加运动活性，也不会减弱尼古丁诱导的敏化。然而，伐尼克兰确实与尼古丁的作用产生交叉敏化，反之亦然。本研究表明伐尼克兰与尼古丁产生剂量依赖性的双向交叉敏化。综上所述，这些发现提供了临床前证据，表明伐尼克兰能够减弱尼古丁的作用，但同时在大鼠中“替代”尼古丁的作用。需要进行纵向研究以观察在临床环境中是否能看到类似的效果，以及这些效果是否有助于伐尼克兰作为戒烟辅助药物的作用。
