Tissue-dependent effects of immunization with a nicotine conjugate vaccine on the distribution of nicotine in rats
Introduction
Vaccines have been studied in animals for the treatment of heroin, cocaine, phencyclidine, nicotine, and amphetamine addiction [1], [2], [3], [4], [5]. These vaccines elicit the production of drug-specific antibodies, which bind drug in serum and extracellular fluid, reduce the unbound drug concentration, and reduce drug distribution to brain. A variety of centrally mediated drug effects and behaviors are thereby blocked or attenuated, including locomotor activation, drug discrimination, and drug self-administration [6], [7], [8], [9], [10]. These animal data suggest a possible role for vaccination in the treatment of drug abuse.
A fundamental requirement for these vaccines to be effective is their ability to reduce drug distribution to brain. Reductions of >50% in drug distribution to brain in the first few minutes after drug administration (the time when the rewarding effects of these drugs are greatest) have been reported for cocaine, phencyclidine, and nicotine [3], [8], [11]. Such reductions have been reported for both active immunization (vaccination) and passive immunization (exogenous administration of drug-specific antibody). These results are surprising that in most cases, the drug doses administered greatly exceeded the estimated binding capacity of the available drug-specific antibody. For example, the self-administration of cocaine in rats was blocked even though the unit cocaine dose exceeded the available cocaine-binding capacity of antibody by 8-fold, and the total cocaine dose administered during a session exceeded the binding capacity by 24- to 48-fold [3], [8], [12]. In rats infused continuously with phencyclidine, a single dose of monoclonal antibody reduced phencyclidine's behavioral toxicity for several weeks despite the daily administration of phencyclidine doses that exceeded the antibody's binding capacity by threefold [13]. In rats vaccinated against nicotine, the distribution of nicotine to brain was reduced by 38% after a single nicotine dose, which exceeded the estimated binding capacity of antibody by 67-fold [14]. These data suggest that vaccination exerts a differential effect on drug distribution to brain, reducing distribution to brain to a greater extent than to other tissues.
Limited data suggest that passive immunization may alter drug distribution to tissues differentially, affecting some tissues more than others. The administration of monoclonal anti-phencyclidine antibodies to rats during chronic phencyclidine infusion produced a substantial and long-lasting reduction in phencyclidine distribution to brain, but only a transient and nonsignificant effect on distribution to testis [13]. Whether a similar phenomenon also occurs with vaccination rather than passive immunization, or against other drugs of abuse, is not known. The extent to which differential effects of immunization on drug distribution to tissues might contribute to the unexpectedly large effect of vaccination on drug distribution to brain is not clear.
Vaccination against nicotine is of interest as a potential treatment for tobacco dependence because of the prevalence and enormous health consequences of this addiction, and because existing treatments are not always effective [15]. The effects of vaccination on nicotine distribution to brain have been studied under a variety of conditions in rats. The early distribution of a single nicotine dose of 0.03 mg/kg (approximately equal to the estimated binding capacity of nicotine-specific antibody) is reduced by up to 64% in vaccinated rats [4], [8]. A similar reduction was seen in rats after a single nicotine dose of 0.03 mg/kg even when those rats also received concurrent chronic nicotine infusion at a rate of 1 mg/kg/day to simulate regular cigarette smoking. This infusion rate provided a daily nicotine dose that exceeded the estimated binding capacity of antibody by 30-fold [16]. A lesser but still significant reduction in brain nicotine concentrations was observed even in rats receiving 2 mg/kg, i.p., as a single nicotine dose, which exceeded the estimated binding capacity of antibody by 67-fold [14]. In addition, vaccination reduces some physiologic or behavioral effects of nicotine, despite the use of nicotine doses that exceed the estimated binding capacity of the antibody [8]. Thus, vaccination against nicotine provides a suitable and well-characterized model for studying the seemingly selective effects of vaccination on drug distribution to brain.
In the current study, the potential mechanisms underlying the effects of vaccination on nicotine distribution to brain were studied by examining the effects of vaccination on nicotine distribution to brain and a variety of additional tissues under both acute and chronic nicotine dosing conditions. Antibody titers in serum and tissues were measured since the presence of nicotine-specific antibody in tissues could affect nicotine distribution to them.
Section snippets
Drugs and reagents
(−)-Nicotine bitartrate, (−)-cotinine, and goat anti-rat immunoglobulin G (IgG)-peroxidase conjugate were obtained from Sigma (St. Louis, MO). Internal standards for the nicotine/cotinine assay were a gift from Dr. Peyton Jacob. Nicotine was administered to rats as nicotine bitartrate, but all doses and measured concentrations are expressed as the base.
Nicotine vaccine
The hapten trans-3′-aminomethylnicotine was prepared as previously described [8] and conjugated at the 3′ position to the carrier protein
Antibody characteristics
The serum nicotine-specific antibody titers (dilutions producing half-maximal optical density on ELISA) for the 1, 5, and 25 min nicotine vaccine groups were 1.4±1.1, 1.0±0.7, and 0.9±0.6×105 (mean±S.D.), respectively, corresponding to mean serum nicotine-specific IgG concentrations of 290±230, 220±150, and 190±130 μg/ml. Two of 30 rats did not achieve titers of 105 (both in the 5 min group) and were not included in the data analysis.
The estimated mean total body nicotine-binding capacity for
Discussion
The main finding of this study was that the effects of vaccination on nicotine distribution varied markedly among tissues. Nicotine distribution to brain was substantially reduced at all time points, with significant but generally smaller reductions to other tissues. However, nicotine distribution to fat (in the single nicotine dose protocol) and lung (in the chronic nicotine infusion protocol) were increased. These data suggest that vaccination reduces nicotine distribution to brain both by
Acknowledgements
Supported by PHS grants DA10714 and U19-DA13327. We thank Nabi for supplying nicotine and control immunogens, and Dr. Peyton Jacob III for supplying analytical standards.
References (34)
- et al.
Effects of passive immunization against morphine on heroin self-administration
Pharmacol. Biochem. Behav.
(1978) - et al.
Generation of anti-(+)methamphetamine antibodies is not impeded by (+)methamphetamine administration during active immunization of rats
Int. Immunopharmacol.
(2001) - et al.
A nicotine conjugate vaccine reduces nicotine distribution to brain and attenuates its behavioral and cardiovascular effects in rats
Pharmacol. Biochem. Behav.
(2000) - et al.
Passive immunization against nicotine attenuates nicotine discrimination
Life Sci.
(2002) - et al.
Vaccination against nicotine during continued nicotine administration in rats: immunogenicity of the vaccine and effects on nicotine distribution to brain
Int. J. Immunopharmacol.
(2000) Determination of affinity and specificity of anti-hapten antibodies by competitive radioimmunoassay
Methods Enzymol.
(1983)- et al.
Improved gas chromatographic method for the determination of nicotine and cotinine in biologic fluids
J. Chromatogr.
(1981) - et al.
Redistribution into plasma of tracer doses of desipramine by anti-desipramine antiserum in rats
Biochem. Pharmacol.
(1987) - et al.
Determination of gallium concentration in “blood-free” tissues using a radiolabeled blood marker
J. Pharm. Sci.
(1985 (Sep.)) - et al.
An oncological view on the blood–testis barrier
Lancet Oncol.
(2002 (June))
Anti-phencyclidine monoclonal Fab fragments reverse PCP-induced behavioral effects and ataxia in rats
J. Pharmacol. Exp. Ther.
Efficacy of a therapeutic cocaine vaccine in rodent models
Nat. Med.
Immunization of rats reduces nicotine distribution to brain
Psychopharmacology
Time course of changes in cocaine self-administration behavior in rats during immunization with the cocaine vaccine IPC-1010
Psychopharmacology (Berl.)
A single dose of monoclonal anti-phencyclidine IgG offers long-term reductions in phencyclidine behavioral effects in rats
J. Pharmacol. Exp. Ther.
Passive immunization against nicotine attenuates dependence as measured by mecamylamine-precipitated withdrawal
Pharmacokinetic mechanisms for obtaining high renal coelimination of phencyclidine and a monoclonal antiphencyclidine antigen-binding fragment of immunoglobulin G in the rat
J. Pharmacol. Exp. Ther.
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