Pentel P R, Dufek M B, Roiko S A, Lesage M G, Keyler D E
Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55422, USA.
J Pharmacol Exp Ther. 2006 May;317(2):660-6. doi: 10.1124/jpet.105.097873. Epub 2006 Jan 11.
Vaccination against nicotine blocks or attenuates nicotine-related behaviors relevant to addiction in rats. Passive immunization with nicotine-specific antibodies is an alternative to vaccination with the potential advantages of allowing control of antibody dose and affinity. In the current study, the effects of two antibodies on the distribution of nicotine to brain were evaluated during chronic nicotine administration in rats; the monoclonal antibody Nic311 (K(d) = 60 nM) and nicotine-specific antiserum (K(d) = 1.6 nM). Nicotine was administered via repeated i.v. bolus doses over 2 days and antibody was administered during the first day. Neither antibody appreciably reduced the chronic accumulation of nicotine in brain, despite high protein binding of nicotine in serum (98.9%) and a 73% reduction in the unbound serum nicotine concentration with the highest Nic311 dose. However, both antibodies substantially reduced the early distribution of nicotine to brain 5 min after a dose. The higher affinity antibody was no more effective than Nic311. The highest Nic311 dose produced serum antibody levels 10 times higher than those reported with vaccination. The efficacy of Nic311 was dose-related, with the highest dose producing a 76% decrease in the early distribution of nicotine to brain. These findings, along with previous data, suggest that the primary effect of passive immunization is to slow, rather than prevent, the distribution of nicotine to brain. In the setting of chronic nicotine dosing, antibodies with a moderate affinity for nicotine produced substantial effects on the early distribution of nicotine to brain and were as effective as higher affinity antibodies.
针对尼古丁的疫苗接种可阻断或减弱大鼠中与成瘾相关的尼古丁行为。用尼古丁特异性抗体进行被动免疫是疫苗接种的一种替代方法，具有可控制抗体剂量和亲和力的潜在优势。在本研究中，在大鼠慢性给予尼古丁期间评估了两种抗体对尼古丁在脑内分布的影响；单克隆抗体Nic311（解离常数K(d)=60 nM）和尼古丁特异性抗血清（K(d)=1.6 nM）。尼古丁通过在2天内重复静脉推注给药，抗体在第一天给药。尽管尼古丁在血清中的蛋白结合率很高（98.9%），且最高剂量的Nic311使未结合的血清尼古丁浓度降低了73%，但两种抗体均未明显降低尼古丁在脑内的慢性蓄积。然而，两种抗体均显著降低了给药后5分钟时尼古丁向脑内的早期分布。高亲和力抗体并不比Nic311更有效。最高剂量的Nic311产生的血清抗体水平比疫苗接种报道的水平高10倍。Nic311的疗效与剂量相关，最高剂量使尼古丁向脑内的早期分布减少了76%。这些发现与先前的数据表明，被动免疫的主要作用是减缓而非阻止尼古丁向脑内的分布。在慢性给予尼古丁的情况下，对尼古丁具有中等亲和力的抗体对尼古丁向脑内的早期分布产生了显著影响，并且与高亲和力抗体一样有效。
