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Active immunization against nicotine alters the distribution of nicotine but not the metabolism to cotinine in the rat

Naunyn-Schmiedeberg's Archives of Pharmacology volume 370, pages 299–304 (2004)Cite this article

Abstract

We have previously shown that active immunization with the nicotine immunoconjugate IP18-KLH attenuates the reinforcing effects of nicotine, i.e., suppresses the nicotine-induced brain dopamine release and prevents reinstatement of the nicotine-seeking behavior in rats. These effects are thought to be due to an alteration of the kinetics of nicotine distribution by the antibodies, resulting in an attenuated nicotine distribution to the brain. In this study, the distribution of nicotine administered at doses corresponding to those used in our previous studies, was investigated in immunized rats and controls. Male Wistar rats received two immunizations with IP18-KLH in Freund’s incomplete adjuvant, 21 days apart, and experiments were performed 7–11 days post-immunization under chloral hydrate anesthesia. Blood samples were collected to determine antibody titer and nicotine selectivity using enzyme-linked immunosorbent assay (ELISA) techniques. The animals received an intravenous nicotine dose and were sacrificed either 3 min or 60 min after nicotine administration. Trunk blood was collected and the brains were removed for analysis of nicotine content. The results showed that immunization against nicotine increases the nicotine concentration in blood and significantly decreases the amount of nicotine that reaches the brain. The present findings thus demonstrate an altered distribution of nicotine after immunization with IP18-KLH. Despite the sustained nicotine binding by the antibodies, the active immunization did not alter the metabolism of nicotine to cotinine, the major nicotine metabolite. In conclusion, the attenuation of the reinforcing effect of nicotine after immunization with IP18-KLH, shown previously, is indeed associated with an altered distribution of nicotine.

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References

  • Benowitz NL, Porchet H, Sheiner L, Jacob P III (1988) Nicotine absorption and cardiovascular effects with smokeless tobacco use: comparison with cigarettes and nicotine gum. Clin Pharmacol Ther 44:23–28

    Google Scholar 

  • Benowitz NL, Porchet H, Jacob P III (1989) Nicotine dependence and tolerance in man: pharmacokinetic and pharmacodynamic investigations. Prog Brain Res 79:279–287

    CAS  PubMed  Google Scholar 

  • De Villiers SH, Lindblom N, Kalayanov G, Gordon S, Malmerfelt A, Johansson AM, Svensson TH (2002) Active immunization against nicotine suppresses nicotine-induced dopamine release in the rat nucleus accumbens shell. Respiration 69:247–253

    Article  PubMed  Google Scholar 

  • Hall W (2002) The prospects for immunotherapy in smoking cessation. Lancet 360:1089–1091

    Article  PubMed  Google Scholar 

  • Henningfield JE, Keenan RM (1993) Nicotine delivery kinetics and abuse liability. J Consult Clin Psychol 61:743–750

    Article  CAS  PubMed  Google Scholar 

  • Hieda Y, Keyler DE, Vandevoort JT, Kane JK, Ross CA, Raphael DE, Niedbalas RS, Pentel PR (1997) Active immunization alters the plasma nicotine concentration in rats. J Pharmacol Exp Ther 283:1076–1081

    CAS  PubMed  Google Scholar 

  • Hieda Y, Keyler DE, VanDeVoort JT, Niedbala RS, Raphael DE, Ross CA, Pentel PR (1999) Immunization of rats reduces nicotine distribution to brain. Psychopharmacology (Berl) 143:150–157

    Article  CAS  Google Scholar 

  • Hieda Y, Keyler DE, Ennifar S, Fattom A, Pentel PR (2000) Vaccination against nicotine during continued nicotine administration in rats: immunogenicity of the vaccine and effects on nicotine distribution to brain. Int J Immunopharmacol 22:809–819

    Article  CAS  PubMed  Google Scholar 

  • Kantak KM, Collins SL, Lipman EG, Bond J, Giovanoni K, Fox BS (2000) Evaluation of anti-cocaine antibodies and a cocaine vaccine in a rat self-administration model. Psychopharmacology (Berl) 148:251–262

    Article  CAS  Google Scholar 

  • Keyler DE, Hieda Y, St Peter J, Pentel PR (1999) Altered disposition of repeated nicotine doses in rats immunized against nicotine. Nicotine Tob Res 1:241–249

    Google Scholar 

  • Khor SP, Mayersohn M (1991) Potential error in the measurement of tissue to blood distribution coefficients in physiological pharmacokinetic modeling. Residual tissue blood. I. Theoretical considerations. Drug Metab Dispos 19:478–485

    CAS  PubMed  Google Scholar 

  • Khor SP, Bozigian H, Mayersohn M (1991) Potential error in the measurement of tissue to blood distribution coefficients in physiological pharmacokinetic modeling. Residual tissue blood. II. Distribution of phencyclidine in the rat. Drug Metab Dispos 19:486–490

    CAS  PubMed  Google Scholar 

  • Langone JJ, Van Vunakis H (1975) Quantitation of continine in sera of smokers. Res Commun Chem Pathol Pharmacol 10:21–28

    CAS  PubMed  Google Scholar 

  • Lindblom N, de Villiers SH, Kalayanov G, Gordon S, Johansson AM, Svensson TH (2002) Active immunization against nicotine prevents reinstatement of nicotine-seeking behavior in rats. Respiration 69:254–260

    Article  CAS  PubMed  Google Scholar 

  • Miller RP, Rotenberg KS, Adir J (1977) Effect of dose on the pharmacokinetics of intravenous nicotine in the rat. Drug Metab Dispos 5:436–443

    CAS  PubMed  Google Scholar 

  • Pentel P, Malin D (2002) A vaccine for nicotine dependence: targeting the drug rather than the brain. Respiration 69:193–197

    Article  CAS  PubMed  Google Scholar 

  • Pentel PR, Malin DH, Ennifar S, Hieda Y, Keyler DE, Lake JR, Milstein JR, Basham LE, Coy RT, Moon JW, Naso R, Fattom A (2000) A nicotine conjugate vaccine reduces nicotine distribution to brain and attenuates its behavioral and cardiovascular effects in rats. Pharmacol Biochem Behav 65:191–198

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This research was supported by the Swedish Research Council (grant no. 4747), the Karolinska Institutet and Independent Pharmaceutica, Stockholm. We wish to thank Mrs Ann-Chatrine Samuelsson for excellent technical assistance. We also wish to thank Consumer Healthcare, Pharmacia (Pfizer), Helsingborg, Sweden, for performing the nicotine and cotinine analyses.

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Affiliations

  1. Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, Nanna Svartz väg 2, 171 77, Stockholm, Sweden

    Sabina H. L. de Villiers, Nina Lindblom & Torgny H. Svensson

  2. Department of Organic Pharmaceutical Chemistry, BMC, Uppsala University, PO Box 574, 751 23, Uppsala, Sweden

    Genadiy Kalayanov, Sandra Gordon & Anette M. Johansson

Authors
  1. Sabina H. L. de Villiers
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  2. Nina Lindblom
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  3. Genadiy Kalayanov
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  4. Sandra Gordon
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  5. Anette M. Johansson
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  6. Torgny H. Svensson
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Corresponding author

Correspondence to Torgny H. Svensson.

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de Villiers, S.H.L., Lindblom, N., Kalayanov, G. et al. Active immunization against nicotine alters the distribution of nicotine but not the metabolism to cotinine in the rat. Naunyn-Schmiedeberg's Arch Pharmacol 370, 299–304 (2004). https://doi.org/10.1007/s00210-004-0960-3

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  • DOI: https://doi.org/10.1007/s00210-004-0960-3

Keywords

  • Tobacco addiction
  • Active immunization
  • Nicotine
  • Distribution
  • Metabolism
  • Rat