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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    • "The most common method is to administer continuous nicotine via osmotic mini-pump to maintain steady-state nicotine levels throughout gestation (Franke et al., 2008; Slotkin et al., 2006; Wei et al., 2011). Pregnant dams are also administered nicotine through drinking water (Pauly et al., 2004; Paz et al., 2007; Zhu et al., 1996), and by IV injection (Harrod et al., 2011; Lacy et al., 2011; LeSage et al., 2006; Pentel et al., 2006). These models provide converging evidence that GN exposure alone produces neurochemical and behavioral changes in offspring (Dwyer et al., 2008). "
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    ABSTRACT: Prenatal tobacco smoke exposure is associated with alterations in motivated behavior in offspring, such as increased consumption of highly palatable foods and abused drugs. Animal models show that gestational nicotine (GN) exposure mediates changes in responding for sucrose and drug reward. A novel, intermittent low-dose intravenous (IV) exposure model was used to administer nicotine (0.05 mg/kg/injection) or saline 3×/day to rats on gestational days 8-21. Two experiments investigated the effect of IV GN on (1) the habituation of spontaneous locomotor activity and on (2) sucrose reinforced responding in offspring. For the operant experiments, animals acquired fixed-ratio (FR-3) responding for sucrose, 26% (w/v), and were tested on varying concentrations (0, 3, 10, 30, and 56%; Latin-square) according to a FR-3, and then a progressive-ratio (PR) schedule. Male and female adult offspring were used. IV GN did not alter birth or growth weight, or the number of pups born. No between-group differences in habituation to spontaneous locomotor activity were observed. FR testing produced an inverted U-shaped response curve, and rats showed peak responding for 10% sucrose reinforcement. Neither gestation nor sex affected responding, suggesting equivalent sensitivity to varying sucrose concentrations. PR testing revealed that GN rats showed greater motivation for sucrose reinforcement relative to controls. A low-dose, IV GN exposure model resulted in increased motivation to respond for sucrose reinforcement in adult offspring. This suggests that using a low number of cigarettes throughout pregnancy will result in increased motivation for highly palatable foods in adult, and perhaps, adolescent offspring.
    Drug and alcohol dependence 02/2012; 124(3):299-306. DOI:10.1016/j.drugalcdep.2012.01.025 · 3.28 Impact Factor
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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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    ABSTRACT: Animal models of tobacco addiction rely on administration of nicotine alone or nicotine combined with isolated constituents. Models using tobacco extracts derived from tobacco products and containing a range of tobacco constituents might more accurately simulate tobacco exposure in humans. To compare the effects of nicotine alone and an aqueous smokeless tobacco extract in several addiction-related animal behavioral models. Nicotine alone and nicotine dose-equivalent concentrations of extract were compared in terms of their acute effects on intracranial self-stimulation (ICSS) thresholds, discriminative stimulus effects, and effects on locomotor activity. Similar levels of nicotine and minor alkaloids were achieved using either artificial saliva or saline for extraction, supporting the clinical relevance of the saline extracts used in these studies. Extract produced reinforcement-enhancing (ICSS threshold-decreasing) effects similar to those of nicotine alone at low to moderate nicotine doses, but reduced reinforcement-attenuating (ICSS threshold-increasing) effects at a high nicotine dose. In rats trained to discriminate nicotine alone from saline, intermediate extract doses did not substitute for the training dose as well as nicotine alone. Locomotor stimulant effects and nicotine distribution to brain were similar following administration of extract or nicotine alone. The reinforcement-attenuating and discriminative stimulus effects of nicotine delivered in an extract of a commercial smokeless tobacco product differed from those of nicotine alone. Extracts of tobacco products may be useful for evaluating the abuse liability of those products and understanding the role of non-nicotine constituents in tobacco addiction.
    Psychopharmacology 09/2011; 220(3):565-76. DOI:10.1007/s00213-011-2514-y · 3.99 Impact Factor
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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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    ABSTRACT: Nicotine vaccines have shown preliminary evidence of efficacy for enhancing smoking cessation rates, but the serum nicotine-specific antibody (NicAb) concentrations produced are highly variable and many subjects do not develop effective levels. As an alternative to vaccination, passive immunization with nicotine-specific monoclonal antibodies could produce more uniform serum NicAb concentrations, but its use is limited by their high cost and shorter elimination half-life. This study investigated supplementing vaccination with monoclonal antibodies in a targeted fashion to increase vaccine efficacy while minimizing the required monoclonal antibody dose. Rats were vaccinated and then given individualized supplemental doses of the nicotine-specific monoclonal antibody Nic311 to achieve a target total serum NicAb concentration known to be effective for blocking locomotor sensitization (LMS) to nicotine. Rats received vaccine, Nic311, both, or neither, followed by 0.3 mg/kg nicotine s.c. for 10 days to produce LMS. Combination immunotherapy completely blocked the development of LMS, while monotherapy with vaccine or Nic311 alone was only minimally effective. Lower brain nicotine levels were associated with reduced locomotor activity averaged over days 7-10. Despite its greater efficacy, combination immunotherapy did not reduce the variability in the resulting total serum NicAb concentrations. Variability in total serum NicAb concentrations was contributed to by both vaccine-generated antibody and by Nic311. These data show that combination immunotherapy, using a Nic311 dose that is by itself only minimally effective, can substantially enhance nicotine vaccine efficacy. However, variability in serum NicAb levels with combination immunotherapy may make translation of this approach challenging.
    International immunopharmacology 07/2011; 11(11):1809-15. DOI:10.1016/j.intimp.2011.07.009 · 2.71 Impact Factor
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