Lindblom N, de Villiers S H L, Kalayanov G, Gordon S, Johansson A M, Svensson T H
Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, Stockholm, Sweden.
Respiration. 2002;69(3):254-60. doi: 10.1159/000063629.
The presently available pharmaceutical aids in smoking cessation possess a rather limited effectiveness. Therefore, we have synthesized a series of immunoconjugates that stimulate the induction of antibodies which may bind nicotine in the blood, thereby preventing it from passing the blood-brain barrier. Thus, the reinforcing action of nicotine in the brain, which is the driving force in tobacco smoking, should be abolished.
The present study was undertaken to test this notion in a long-term relapse model in rats, measuring the reinstatement of nicotine-seeking behavior, following active immunization with IP18-KLH, one of our immunoconjugates.
Male Wistar rats were immunized with a nicotine-KLH conjugate (nicotine immunogen) and Freund's adjuvant after having been trained to meet the criteria of stable nicotine self-administration on a fixed ratio (FR3) schedule. The rats were subsequently extinguished from nicotine self-administration behavior and finally, as extinction was completed, they were exposed to small, priming doses of nicotine, which previously have been shown to reinstate the nicotine-seeking behavior. The antibody titers were measured by ELISA.
It was found that rats with high titers (>1:10,000) of antibodies against nicotine, in contrast to those with low/no nicotine selective antibodies, do not reinstate nicotine self-administration behavior when they are exposed to nicotine.
Our findings indicate that active immunization against nicotine may effectively abolish the reinforcing action of nicotine in brain, an effect which is critical for relapse in nicotine dependence. These data suggest the potential utility of active immunization in smoking cessation programs.
目前可用的戒烟药物辅助手段效果相当有限。因此，我们合成了一系列免疫缀合物，这些免疫缀合物可刺激抗体的诱导产生，这些抗体可能会结合血液中的尼古丁，从而阻止其通过血脑屏障。这样，尼古丁在大脑中的强化作用（这是吸烟的驱动力）就应该被消除。
本研究旨在通过大鼠长期复发模型来验证这一概念，测量在用我们的一种免疫缀合物IP18-KLH进行主动免疫后，尼古丁寻求行为的恢复情况。
雄性Wistar大鼠在按照固定比率（FR3）方案训练至符合稳定尼古丁自我给药标准后，用尼古丁 - KLH缀合物（尼古丁免疫原）和弗氏佐剂进行免疫。随后使大鼠停止尼古丁自我给药行为，最后，在停止给药完成后，让它们接触小剂量的启动剂量尼古丁，之前已证明这种剂量会恢复尼古丁寻求行为。通过酶联免疫吸附测定法测量抗体滴度。
发现与那些具有低/无尼古丁选择性抗体的大鼠相比，具有高滴度（>1:10,000）抗尼古丁抗体的大鼠在接触尼古丁时不会恢复尼古丁自我给药行为。
我们的研究结果表明，针对尼古丁的主动免疫可能有效地消除尼古丁在大脑中的强化作用，这一作用对尼古丁依赖的复发至关重要。这些数据表明主动免疫在戒烟计划中的潜在效用。
