Marks M J, Stitzel J A, Collins A C
J Pharmacol Exp Ther. 1985 Dec;235(3):619-28.
The experiments reported here examined the time course of the development and loss of tolerance to nicotine as well as the time course for the up-regulation and return to basal levels of brain nicotinic receptors. Nicotine was administered by continuous i.v. infusion through cannulae implanted in the right jugular veins of DBA mice. Tolerance to the effects of nicotine on Y-maze activity and rears, body temperature and heart rate was seen accompanying the infusion of 4 mg/kg/hr of nicotine. Maximal tolerance was obtained in 4 days and was paralleled by increases in the number of brain nicotine binding sites. The binding of alpha-bungarotoxin was also increased by chronic nicotine treatment but increases in binding preceded the development of detectable tolerance to the challenge dose of nicotine. Chronic nicotine treatment had no effect on quinuclidinyl benzilate binding. Tolerance to the effects of nicotine was lost at different rates for the various tests in that base-line response was attained for the Y-maze activity and rearings test in 8 days, whereas 12 to 16 days were required to regain control response for the body temperature test. Tolerance for the heart rate test persisted throughout the 20-day withdrawal period. Brain nicotine binding sites had returned to control levels by 8 days after treatment whereas the alpha-bungarotoxin binding sites were at control levels at the earliest time of postinfusion testing (4 days). Brain quinuclidinyl benzilate binding sites were unaffected by nicotine treatment and did not change during the withdrawal period. The changes in nicotine binding in the various brain regions during the onset and offset experiments were virtually identical. These changes in binding correlated highly with the acquisition and loss of tolerance to the effects of nicotine on the Y-maze locomotor activity and body temperature tests. The correlations between changes in nicotine binding and the Y-maze rearings and the heart rate tests were lower but some association is suggested. Although changes in nicotine binding may explain some of the tolerance observed, other explanations for tolerance must be sought as well.
本文所报道的实验研究了对尼古丁耐受性的发展与丧失的时间进程，以及脑烟碱受体上调和恢复至基础水平的时间进程。通过植入DBA小鼠右颈静脉的套管以静脉持续输注的方式给予尼古丁。在以4mg/kg/小时的速度输注尼古丁的过程中，观察到对尼古丁对Y迷宫活动、竖毛、体温和心率影响的耐受性。4天内获得最大耐受性，同时脑尼古丁结合位点数量增加。慢性尼古丁处理也增加了α-银环蛇毒素的结合，但结合增加先于对尼古丁激发剂量可检测到的耐受性的发展。慢性尼古丁处理对喹核酯结合没有影响。对于各种测试，对尼古丁作用的耐受性以不同速率丧失，Y迷宫活动和竖毛测试在8天内恢复到基线反应，而体温测试则需要12至16天才能恢复对照反应。心率测试的耐受性在整个20天的戒断期持续存在。处理后8天脑尼古丁结合位点已恢复到对照水平，而α-银环蛇毒素结合位点在输注后最早测试时间（4天）即处于对照水平。脑喹核酯结合位点不受尼古丁处理影响，在戒断期也没有变化。在开始和停止实验期间，不同脑区尼古丁结合的变化几乎相同。这些结合变化与对尼古丁对Y迷宫运动活动和体温测试作用的耐受性的获得和丧失高度相关。尼古丁结合变化与Y迷宫竖毛和心率测试之间的相关性较低，但仍表明存在某种关联。虽然尼古丁结合的变化可能解释了观察到的一些耐受性，但也必须寻找其他耐受性的解释。
