Immunization of rats reduces nicotine distribution to brain
Immunization of rats reduces nicotine distribution to brain
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DOI：
10.1007/s002130050930
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发表时间：
1999-04-01
影响因子：
3.4
通讯作者：
Pentel, PR
中科院分区：
文献类型：
--
作者：
Hieda, Y;Keyler, DE;Pentel, PR
在麻醉大鼠上研究了尼古丁主动免疫对尼古丁脑内初始分布的影响。动物经颈静脉快速注射尼古丁0.03 mg/kg（相当于吸两支香烟的人吸收的尼古丁剂量）。在对照动物中，动脉血清尼古丁浓度最初超过静脉浓度4.6倍，类似于人类吸烟产生的初始动静脉差异。用尼古丁类似物CMUNic免疫的动物保持这种动静脉梯度。但动脉和静脉的尼古丁浓度比对照组高几倍。即使在第一次（7.5 s）采样时间，免疫动物的动脉尼古丁浓度也较高。免疫动物3分钟时的脑尼古丁浓度降低了36%。在第二组动物中研究尼古丁分布到大脑的时间过程。在尼古丁给药后立即进行的整个6分钟采样期间，CMUNic免疫大鼠的脑尼古丁浓度降低（平均降低38%）。在最早的采样时间（30 s）发现减少，在1 min时最大（48%）。与对照组相比，CMUNic免疫动物血清中尼古丁蛋白结合率显著增加（91.2% vs 10.9%），血清中未结合尼古丁浓度较低（10.0ng/ml vs 13.4ng/ml）。脑尼古丁浓度的降低与抗体对尼古丁的亲和力和血清中结合尼古丁的百分比相关。这些数据表明，通过主动免疫产生的尼古丁特异性抗体可快速结合动脉血中的尼古丁，降低未结合尼古丁浓度，并减少尼古丁向脑的早期分布。使用临床相关尼古丁剂量和给药途径观察到效应。这些数据表明，使用免疫来改变尼古丁的行为效应是可能的。
The effect of active immunization against nicotine on the initial distribution of nicotine to brain was studied in anesthetized rats. Animals received nicotine 0.03 mg/kg nicotine (equivalent to the nicotine dose absorbed by a human smoking two cigarettes) as a rapid injection in the jugular vein. In control animals, the arterial serum nicotine concentration initially exceeded the venous concentration 4.6-fold, similar to the initial arteriovenous difference produced by cigarette smoking in humans. Animals immunized with the nicotine analog CMUNic maintained this arteriovenous gradient. but with both arterial and venous nicotine concentrations several times higher than in controls. The arterial nicotine concentration was higher in immunized animals even at the first (7.5 s) sampling time. The brain nicotine concentration at 3 min was 36% lower in the immunized animals. The time course of nicotine distribution to brain was studied in a second group of animals. Brain nicotine concentration was reduced in rats immunized with CMUNic over the entire 6-min sampling period immediately following nicotine dosing (mean reduction 38%). A reduction was found at the earliest sampling time (30 s) and was maximal at 1 min (48%). Nicotine protein binding in serum was markedly increased in animals immunized with CMUNic compared to controls (91.2 versus 10.9%), and the unbound nicotine concentration in serum was lower (10.0 versus 13.4 ng/ml). The reduction in brain nicotine concentration correlated with antibody affinity for nicotine, and the percentage of nicotine bound in serum, These data demonstrate that nicotine-specific antibodies produced by active immunization rapidly bind nicotine in arterial blood, reduce the unbound nicotine concentration, and reduce the early distribution of nicotine to brain, Effects were observed using a clinically relevant nicotine dose and route of administration. These data suggest that the use of immunization to modify the behavioral effects of nicotine may be possible.