Combined Active and Passive Immunization Enhances the Efficacy of Immunotherapy against Nicotine in Rats
- Minneapolis Medical Research Foundation, Minneapolis, Minnesota (S.A.R., A.C.H., D.E.K., M.G.L., P.R.P.); Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (D.E.K.); and Departments of Pharmacology (S.A.R., P.R.P.), Biostatistics (Y.Z.), and Medicine (A.C.H., M.G.L., P.R.P.), University of Minnesota Medical School, Minneapolis, Minnesota
- Address correspondence to:
Dr. Paul Pentel, Department of Medicine, G5, Hennepin County Medical Center, 701 Park Ave. S., Minneapolis, MN 55422. E-mail: pentel{at}umn.edu
Abstract
Vaccination against nicotine reduces the behavioral effects of nicotine in rats, and it is under clinical evaluation as a treatment for tobacco addiction. Efficacy is limited by the need for high serum nicotine-specific antibody (NicAb) levels, and currently available nicotine vaccines do not uniformly generate the required NicAb levels. Passive immunization with a nicotine-specific monoclonal antibody (Nic311) has also shown efficacy in rats. The principal aim of this study was to determine whether the combined use of vaccination and passive immunization would produce greater effects than vaccination alone on nicotine pharmacokinetics and locomotor sensitization (LMS) to nicotine. Rats were treated with vaccination alone, Nic311 alone, both, or neither, and then they were administered 10 daily injections of 0.3 mg/kg nicotine s.c. Treatment with Nic311 or vaccination alone increased the binding of nicotine in serum, reduced the unbound serum nicotine concentration and nicotine distribution to brain, and attenuated the development of LMS. Combined use of vaccination and passive immunization produced higher total serum NicAb levels, greater changes in nicotine pharmacokinetics, and a greater attenuation of LMS than either treatment alone. The total serum NicAb concentration was significantly correlated with brain nicotine levels and locomotor activity. These data indicate that providing higher serum NicAb concentrations improves the efficacy of immunotherapy against nicotine and that supplementing vaccination with passive immunization is a potential strategy to accomplish this.
Footnotes
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This study was supported by National Institute on Drug Abuse Grants DA10714, F31-DA021946, F32-DA021935, T32-DA07097, and P50-DA013333.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.135111.
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ABBREVIATIONS: NicAb, nicotine-specific antibody; Nic311, nicotine-specific monoclonal antibody 311; LMS, locomotor sensitization; 3′-AmNic, 3′-aminomethyl nicotine; rEPA, recombinant Pseudomonas exoprotein A; 3′-AmNic-rEPA, 3′-aminomethyl nicotine conjugated to recombinant Pseudomonas exoprotein A; ELISA, enzyme-linked immunosorbent assay; HRP, horseradish peroxidase; ANOVA, analysis of variance.
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- Received December 12, 2007.
- Accepted February 26, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
