Macnamara Claire L, Holmes Nathan M, Westbrook R Fred, Clemens Kelly J
School of Psychology, University of New South Wales, Sydney, Australia.
School of Psychology, University of New South Wales, Sydney, Australia.
Neuropharmacology. 2016 Jun;105:463-470. doi: 10.1016/j.neuropharm.2016.02.023. Epub 2016 Feb 18.
Varenicline is a partial nicotine receptor agonist widely prescribed as a smoking cessation medication. Repeated (or long-term) use of varenicline has been proposed as a treatment option for tobacco addiction. However the effect of repeated varenicline use on motivation for nicotine is unknown. Here the intravenous nicotine self-administration paradigm in rats was used to model the consequences of varenicline treatment across repeated cycles of administration, extinction and reinstatement. Rats acquired nicotine self-administration across 20 days before undergoing 6 days of extinction, where each extinction session was preceded by a single injection of varenicline or saline. This was followed by a single varenicline-free nicotine-primed reinstatement test. All rats then reacquired nicotine self-administration for 10 days followed by a second cycle of extinction. Across this period, rats either received a second cycle of varenicline (VAR-VAR) or saline (SAL-SAL), or the alternative treatment (SAL-VAR, VAR-SAL), followed by a final reinstatement test. Treatment with varenicline increased responding across the first cycle of extinction, but did not affect responding in the reinstatement test. Across the second cycle, varenicline again increased responding across extinction, and critically, rats treated with varenicline across cycle 1 and saline across cycle 2 (Group VAR-SAL) exhibited more reinstatement than rats in any other group. The effect of VAR on nicotine seeking was not due to its effects on locomotor activity. Instead, the results suggest that a history of VAR can increase vulnerability to reinstatement/relapse when its treatment is discontinued. The possible mechanisms of this increased vulnerability are discussed.
伐尼克兰是一种部分烟碱受体激动剂，被广泛用作戒烟药物。反复（或长期）使用伐尼克兰已被提议作为治疗烟草成瘾的一种选择。然而，反复使用伐尼克兰对烟碱动机的影响尚不清楚。在此，利用大鼠静脉注射烟碱自我给药范式来模拟伐尼克兰治疗在给药、戒断和复吸的反复周期中的后果。大鼠在接受6天的戒断之前，经过20天获得烟碱自我给药，其中每次戒断实验前均单次注射伐尼克兰或生理盐水。随后进行一次无伐尼克兰的烟碱激发复吸试验。所有大鼠随后再次获得烟碱自我给药10天，接着是第二个戒断周期。在此期间，大鼠要么接受第二个伐尼克兰周期（VAR-VAR）或生理盐水周期（SAL-SAL），要么接受交替治疗（SAL-VAR，VAR-SAL），随后进行最后一次复吸试验。伐尼克兰治疗在第一个戒断周期中增加了反应，但在复吸试验中未影响反应。在第二个周期中，伐尼克兰再次增加了戒断期间的反应，关键的是，在第一个周期接受伐尼克兰治疗而在第二个周期接受生理盐水治疗的大鼠（VAR-SAL组）比其他任何组的大鼠表现出更多的复吸。伐尼克兰对寻求烟碱的作用并非因其对运动活动的影响。相反，结果表明，伐尼克兰治疗史可增加在其治疗停止时复吸/复发的易感性。讨论了这种易感性增加的可能机制。
