Differential Effects of Passive Immunization with Nicotine-Specific Antibodies on the Acute and Chronic Distribution of Nicotine to Brain in Rats

Abstract

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 ϭ 60 nM) and nicotine-specific antiserum (K d ϭ 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.

Changes in maternal and fetal nicotine distribution after maternal administration of monoclonal nicotine-specific antibody to rats

“…Similar results have been obtained with vaccination against nicotine in adult male rats [25] or pregnant females [15], and with Nic311 administration in adult male rats [26]. The consistency of this finding in adult animals strongly supports the hypothesis that nicotine-specific antibodies serve primarily to slow nicotine distribution to brain rather than to prevent it.…”

“…However, this study used only a single dose of nicotine. The higher affinity of this antiserum for nicotine could have contributed to the decrease in whole fetus nicotine levels, but this advantage would likely not have been maintained with chronic nicotine dosing because a previous study comparing Nic311 and this same rabbit antiserum in adult male rats showed no differences in effects on nicotine distribution between the antiserum and Nic311 during chronic nicotine dosing [26].…”

“…There is considerable reluctance to use standard smoking cessation medications (nicotine replacement therapy, bupropion, nortripyline) during pregnancy because of concerns about their potential adverse effects. Immunization against nicotine is appealing in this regard because the antibodies elicited are highly specific for nicotine and do not cross react with any as yet identified endogenous compounds or structures [11,26], and immunization against several infectious diseases is already used safely during pregnancy [32]. Whether maternal immunization prior to or during pregnancy would be safe for the fetus depends upon its net effects on nicotine distribution to the fetus.…”

Combined Active and Passive Immunization Enhances the Efficacy of Immunotherapy against Nicotine in Rats

“…The effects of vaccination and of passive immunization on nicotine pharmacokinetics in rats are qualitatively similar (Hieda et Pentel et al, 2006), but they have not previously been directly compared. A comparison of vaccination using 3Ј-AmNic-rEPA and passive immunization using Nic311 was feasible because the affinity of NicAbs elicited by vaccination is similar to that of Nic311, and the dosing regimen of Nic311 used in the LMS experiment produced serum NicAb levels equal to those generated by vaccination.…”

The Fate and Function of Therapeutic Antiaddiction Monoclonal Antibodies across the Reproductive Cycle of Rats

“…Another advantage is that anti-PCP and anti-METH mAbs do not seem to cross blood-organ barriers such as the brain and testis to any great extent, but they do effectively remove PCP and METH from these organs (Proksch et al, 2000;Laurenzana et al, 2003a). This redistribution of target drug out of brain tissue is the mechanism of action for the neuroprotection mediated by these antiaddiction mAb medications (Laurenzana et al, 2003b;Keyler et al, 2006;Pentel et al, 2006). These findings suggest the potential for similar effects at the maternal blood-brain barrier, fetal blood-brain barrier, and blood-placental barrier, as suggested by studies in nearterm, nicotine-treated pregnant rats (Keyler et al, 2005a,b).…”