Reduced nicotine distribution from mother to fetal brain in rats vaccinated against nicotine: Time course and influence of nicotine dosing regimen
Introduction
Vaccination or passive immunization (transfer of heterologous drug-specific antibody) is being studied as a potential treatment for drug addiction. Vaccination elicits the production of high affinity drug-specific antibodies which bind drug in serum and extracellular fluid, reduce drug distribution to brain and attenuate the drug's behavioral effects [1], [2], [3], [4], [5], [6]. Vaccination or passive immunization has been shown to reduce nicotine, cocaine or phencyclidine-induced locomotor activation [6], [7], [8], the discriminative stimulus properties of nicotine [4], [9], reinstatement of nicotine self-administration [10], and the maintenance of cocaine or methamphetamine self-administration [11], [12]. Clinical trials of vaccines for cocaine and nicotine addiction have been initiated [13] (S. Winston, personal communication).
The safety profile of vaccines or passive immunization for addictive drugs is favorable. Because the elicited antibodies do not appreciably enter the brain [14], immunization circumvents the central nervous system side effects common to many other potential pharmacotherapies for drug addiction. The high degree of binding specificity of these antibodies also minimizes potential side effects outside of the central nervous system. No important adverse effects of either vaccination or passive immunization have been found to date in either animals or in early clinical trials [13], [15].
While side effects of vaccination or passive immunization have not been identified, few data are available regarding the safety of immunization during or prior to pregnancy. Adverse effects of the antibody per se on the fetus are not expected [16]. However, addictive drugs may have important adverse effects on fetal viability and development. Nicotine is a teratogen in rats, and gestational exposure to nicotine in rats has been associated with altered c-fos expression [17] and neurotransmitter concentrations [18] in fetal brain, altered locomotor activity in pups [19], and altered responses to hypoxia in pups [20]. In humans, smoking during pregnancy is associated with spontaneous abortion, low birth weight, increased neonatal mortality, sudden infant death syndrome and the development of behavioral problems including conduct disorder, attention deficit hyperactivity disorder, and an increased risk of becoming a smoker in young adults [21], [22]. Animal and human studies suggest adverse outcomes after gestational exposure to cocaine or methamphetamine as well [23], [24]. It is therefore important to understand whether immunization alters fetal exposure to these drugs. Because fetal brain is a specific target for many of these adverse effects, the effects of immunization on drug distribution to fetal brain is of particular interest.
In a previous study, vaccination of female rats (prior to mating and pregnancy) reduced the early distribution of a single dose of nicotine administered on gestational day (GD) 16–22 to fetal brain [25]. Passive immunization of pregnant rats with heterologous nicotine-specific IgG just prior to nicotine dosing on GD16-22 was similarly effective. However, only passive immunization reduced nicotine transfer to the whole fetus. These data suggested that immunization might reduce nicotine distribution to fetal brain either by reducing total nicotine distribution to the fetus, or by altering nicotine distribution within the fetus. Because serum antibody concentrations and nicotine binding in fetal serum were not measured, the underlying mechanisms and the reasons for differences between vaccination and passive immunization remain unclear. The previous study also examined only a single nicotine dose and a single time interval (5 min) from nicotine dosing to sampling.
The current study expands upon previous data by examining the time course of vaccination effects on nicotine distribution to the fetus, and the effects of vaccination on nicotine distribution under a variety of acute and chronic nicotine dosing conditions which approximate nicotine exposure in smokers. Measures of maternal and fetal antibody concentrations and nicotine protein binding were obtained to estimate antibody transfer to the fetus and to elucidate the mechanisms by which vaccination alters nicotine distribution to fetal brain.
Section snippets
Drugs and reagents
(−)-Nicotine bitartrate, (−)-cotinine, and polyvinyl pyrrolidone were obtained from Sigma (St. Louis, MO). 3H-(−)-nicotine was obtained from New England Nuclear. Goat anti-rat IgG-peroxidase conjugate was obtained from Jackson Immunoresearch. Internal standards for nicotine and cotinine assay were provided by Dr. Peyton Jacob. All nicotine doses are expressed as weight of the base.
Nicotine-vaccine (Nic-vaccine)
Nicotine-vaccine was prepared by conjugating the hapten trans-3′-aminomethylnicotine at the 3′ position to the
Protocol 1: single dose nicotine, 5 min
Most rats became pregnant within 2 weeks of their fourth vaccine dose, so that GD20 occurred 4–5 weeks after the 4th vaccine dose. The mean maternal and fetal serum nicotine-specific antibody concentrations are shown in Table 1. All rats included in this protocol had maternal serum antibody concentrations above 30 μg/ml. Maternal and fetal serum nicotine-specific antibody concentrations were highly correlated (Fig. 1, top), with a maternal/fetal concentration ratio of approximately 10:1. The
Discussion
The main findings of this study are that (1) vaccination reduced nicotine distribution to fetal brain for up to 25 min after a single nicotine dose, (2) vaccine effects on nicotine distribution were greater after a single nicotine dose than after chronic nicotine dosing by either continuous infusion or repeated bolus doses, (3) the transfer of nicotine-specific antibody from mother to fetus was limited but sufficient to enhance the binding of nicotine in fetal serum and reduce nicotine
Acknowledgement
Supported by NIDA grants DA15668, DA10714, P50-DA13333 and P50-HL61193.
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