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Differential effects of passive immunization with nicotine-specific antibodies on the acute and chronic distribution of nicotine to brain in rats

Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55422, USA.
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.86). 06/2006; 317(2):660-6. DOI: 10.1124/jpet.105.097873
Source: PubMed

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) = 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.

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    • "infusion of either saline or nicotine alone (3.2 mg kg −1 day −1 ), some rats in Experiment 3a (see below) had received an i.v. infusion of control immunoglobin or the nicotine-specific monoclonal antibody Nic311 (see Keyler et al. 2005; Pentel et al. 2006), and all rats in Experiment 3b had received prior exposure to restraint stress. However, rats were treatment free and their performance had been maintained under their respective behavioral assay for 4–9 weeks before beginning the present experiments (32±6, 41±6, and 65±19 days [mean ± SEM] for Experiments 2, 3a, and 3b, respectively). "
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    • "Nic311 was purified by protein G chromatography to ≥ 95% protein content with endotoxin levels of < 0.2 enzyme unit/mg and diluted in phosphate-buffered saline. Nic311 has previously been characterized as an IgG 1κ with K d = 60 nM for nicotine and <1% crossreactivity with cotinine, nicotine-N-oxide or acetylcholine [17]. Control IgG was human polyclonal IgG (Gammagard; Baxter Healthcare Corp., Westlake Village, CA) that does not bind nicotine or influence nicotine pharmacokinetics or behavior [18] "
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