长期给予伐伦克林对雄性 P 大鼠乙醇和蔗糖觅药和自身给药的影响。
The Effects of Long-Term Varenicline Administration on Ethanol and Sucrose Seeking and Self-Administration in Male P Rats.
机构信息
Department of Psychology, Indiana University Purdue University Indianapolis, Indianapolis, Indiana.
Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
出版信息
Alcohol Clin Exp Res. 2018 Feb;42(2):453-460. doi: 10.1111/acer.13562. Epub 2017 Dec 23.
BACKGROUND
Varenicline, a partial agonist at α4β2 and full agonist at α7 nicotinic cholinergic receptors, is FDA-approved for treatment of smoking cessation and has been found to reduce alcohol craving in clinical populations. In rodents, varenicline decreases free-choice ethanol (EtOH) intake with somewhat mixed findings in operant paradigms that utilize a combined appetitive/consummatory response.
METHODS
The present experiment utilized an operant paradigm that procedurally separates appetitive from consummatory responding and a "reward-blocking" approach (i.e., rats were able to consume EtOH during treatment) to better understand the efficacy of varenicline as a treatment for EtOH self-administration and subsequent EtOH seeking. Separate groups of EtOH- and sucrose-reinforced alcohol-preferring, male P rats experienced alternating cycles of vehicle (2-week cycles) and varenicline (0.3, 1.0, and 2.0 mg/kg self-administered in a gelatin preparation) treatment (3-week cycles) prior to daily sessions where a single lever press resulted in 20 minutes of reinforcer access. At the end of each cycle, a single extinction session assessed the seeking response in the absence of drug pretreatment.
RESULTS
Varenicline dose dependently decreased EtOH intake. Sucrose intake was largely unaffected, with no overall treatment effects and only sporadic days where the medium and high dose differed from vehicle. Neither sucrose nor EtOH seeking was significantly decreased by varenicline, and there were no treatment effects on either lick or lever-press latency. Overall effect sizes were much greater for both drinking and seeking in the EtOH group as compared to the sucrose group.
CONCLUSIONS
Varenicline effectively attenuates EtOH self-administration during treatment, but the experience with EtOH consumption while varenicline is "on board" is not sufficient to alter subsequent EtOH seeking. The overall pattern of findings indicates that varenicline blocks the rewarding properties of EtOH while not substituting for EtOH, that the nonspecific effects on an alternate reinforcer are negligible, and that blood levels of varenicline need to be maintained in order for treatment to remain effective.
背景
伐伦克林是一种 α4β2 型部分激动剂和 α7 型烟碱型乙酰胆碱受体完全激动剂，已被美国食品和药物管理局批准用于戒烟治疗，并已被发现可减少临床人群的酒精渴求。在啮齿动物中，伐伦克林可减少自由选择的乙醇（EtOH）摄入，但在使用联合奖赏/消耗反应的操作性范式中，其结果有些混杂。
方法
本实验利用了一种操作性范式，该范式程序性地将奖赏与消耗反应分开，并采用“奖励阻断”方法（即，大鼠在治疗期间可以消耗 EtOH），以更好地理解伐伦克林作为治疗 EtOH 自我给药和随后的 EtOH 寻求的疗效。一组单独的 EtOH 和蔗糖强化的酒精偏好雄性 P 大鼠经历了交替的载体（2 周周期）和伐伦克林（0.3、1.0 和 2.0mg/kg 在明胶制剂中自我给药）治疗（3 周周期），然后进行每日治疗，其中单次按压杠杆会导致 20 分钟的强化物访问。在每个周期结束时，进行单次消退治疗，以评估药物预处理缺失时的寻求反应。
结果
伐伦克林剂量依赖性地减少了 EtOH 摄入。蔗糖摄入量基本不受影响，没有整体治疗效果，只有少数几天中中剂量和高剂量与载体不同。伐伦克林对蔗糖或 EtOH 的寻求均未显著减少，并且对舔或杠杆按压潜伏期均无治疗作用。与蔗糖组相比，EtOH 组的饮酒和寻求总体效应大小要大得多。
结论
伐伦克林在治疗期间有效减轻了 EtOH 的自我给药，但在伐伦克林“起作用”时的 EtOH 消耗经验不足以改变随后的 EtOH 寻求。总体研究结果表明，伐伦克林阻断了 EtOH 的奖赏特性，而不替代 EtOH，对替代强化物的非特异性影响可以忽略不计，并且需要维持伐伦克林的血药水平才能使治疗保持有效。
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