Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania 15219-3143, USA.
Chronobiol Int. 2013 Aug;30(7):855-69. doi: 10.3109/07420528.2013.782314. Epub 2013 May 22.
Chronic daily administration of nicotine and other drugs of abuse has been found to entrain pre- and post-drug circadian locomotor activity episodes that oscillate on a 24-h schedule and persist for several days after administration ceases. This drug-entrainable oscillator system could conceivably lead to circadian rhythms of drug seeking and drug use in human drug addicts. The present study (1) characterizes the ability of daily nicotine administration to entrain circadian wheel-running activity episodes in rats across a range of doses, lighting schedules, and food access; and (2) tests whether pre- and post-nicotine episodes can be altered through pharmacological manipulations. Adult female rats were housed in wheel boxes for 35-60 d, and both wheel-running and feeding-related behaviors were measured continuously. Following acclimation, nicotine or saline was administered for 16-24 d, and the rats were left undisturbed for several test days to observe the persistence of nicotine-entrained activity. The results showed that nicotine dose-dependently entrains wheel-running activity, and the highest dose of 1.0 mg/kg produces robust pre- and post-nicotine circadian activity episodes under constant, fixed, and variable light/dark schedules. In the pharmacological manipulation experiment, nicotine-entrained rats were administered one of seven pharmacological treatments (varenicline, mecamylamine, acamprosate, topiramate, naltrexone, SB-334867, or bupropion) in place of the nicotine injection for 2 d, and the rats were not disturbed for four subsequent days. Most of the treatment drugs significantly reduced post-nicotine activity episodes, but only three treatments affected pre-nicotine episodes: the μ- and κ-opioid receptor antagonist naltrexone, the orexin-1 receptor antagonist SB-334867, and the AMPA (2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid)/kainate antagonist topiramate. These results show that chronic daily nicotine administration is a robust zeitgeber that dose-dependently entrains a nonphotic oscillator system that includes opioid, orexin, and glutamate pathways.
慢性每日给予尼古丁和其他药物滥用已被发现使药物给药前和给药后的昼夜节律性运动活动期受药物控制，这些活动期以 24 小时的时间表为周期，并在给药停止后持续数天。这种药物可诱导的振荡器系统可能导致人类药物滥用者的药物寻求和药物使用的昼夜节律。本研究：（1）描述了在一系列剂量、光照时间表和食物摄入条件下，每日给予尼古丁使大鼠昼夜节律性轮跑活动期受药物控制的能力；（2）测试了通过药理学手段是否可以改变尼古丁给药前后的活动期。成年雌性大鼠被饲养在轮箱中 35-60 天，并连续测量轮跑和摄食相关行为。适应后，给予尼古丁或盐水 16-24 天，然后让大鼠不受干扰地进行几天测试，以观察尼古丁诱导的活动期的持续时间。结果表明，尼古丁剂量依赖性地诱导轮跑活动，最高剂量 1.0mg/kg 在恒光、固定光/暗时间表和可变光/暗时间表下产生强烈的给药前和给药后昼夜节律性活动期。在药理学操作实验中，用七种药理学处理之一（伐尼克兰、美加仑、安非他酮、托吡酯、纳曲酮、SB-334867 或安非他酮）替代尼古丁注射，给予尼古丁诱导的大鼠 2 天，然后连续四天不干扰大鼠。大多数治疗药物显著减少了给药后尼古丁的活动期，但只有三种治疗药物影响了给药前的尼古丁活动期：μ-和 κ-阿片受体拮抗剂纳曲酮、食欲素-1 受体拮抗剂 SB-334867 和 AMPA（2-氨基-3-（3-羟基-5-甲基异恶唑-4-基）丙酸）/海人藻酸受体拮抗剂托吡酯。这些结果表明，慢性每日给予尼古丁是一种强有力的时间信号，它依赖性地诱导一个包括阿片、食欲素和谷氨酸途径的非光振荡器系统。
