This project is part of an ongoing multi-laboratory effort to evaluate the potential of immunization against nicotine to aid in smoking cessation. The nicotine conjugate immunogen, developed by Nabi, is 3'- aminomethylnicotine-rEPA. The particular role of this laboratory has been to evaluate whether sufficient immunization could be achieved to eliminate a variety of nicotine's behavioral and physiological effects. Passive immunization with IgG from anti-sera raised against this immunogen has largely eliminated the pressor effect of nicotine, the locomoter activating effect and the ability of nicotine to relieve nicotine abstinence syndrome (all at nicotine mg/kg doses higher than those consumed by smokers). Preliminary data suggests that active immunization can significantly reduce the nicotine pressor effect. All this is consistent with data from Dr. Pentel's laboratory demonstrating that immunization profoundly interferes with nicotine distribution. In anticipation of clinical studies, Nabi will prepare a Clinical (or GMP) Lot of immunogen and our own laboratory will address several issues of preclinical relevance. Can antibodies raised against the Clinical Lot of immunogen prevent various nicotine actions in a manner similar to that already demonstrated for antibodies raised against the research lot? Can active immunization, discriminative stimulus properties and the initial induction of nicotine dependence? In the cases of cardiovascular and locomoter actions, does the Clinical Lot of immunogen have similar effects to those found initially with the Research Lot? Several studies address the possible use of immunization prior to smoking cessation and during ongoing nicotine consumption. Will passive immunization or active immunization precipitate nicotine abstinence signs during ongoing nicotine infusion? Or will the gradual onset of immunization result in equally gradual waning of dependence, so as to attenuate the subsequent abstinence syndrome once nicotine is abruptly discontinued? In several experiments, samples of serum and brain tissue will be obtained and shipped to Dr. Pentel (another project leader) for analysis of antibody concentration and affinity as well as serum and brain nicotine levels. These joint experiments are intended to increase our understanding of the quantitative relationships between antibody levels, changes in nicotine distribution and modulation of nicotine pharmacodynamic effects.
| LeSage, Mark G; Keyler, Daniel E; Hieda, Yoko et al. (2006) Effects of a nicotine conjugate vaccine on the acquisition and maintenance of nicotine self-administration in rats. Psychopharmacology (Berl) 184:409-16 |
| Hatsukami, Dorothy K; Rennard, Stephen; Jorenby, Douglas et al. (2005) Safety and immunogenicity of a nicotine conjugate vaccine in current smokers. Clin Pharmacol Ther 78:456-67 |
| Satoskar, S D; Keyler, D E; LeSage, M G et al. (2003) Tissue-dependent effects of immunization with a nicotine conjugate vaccine on the distribution of nicotine in rats. Int Immunopharmacol 3:957-70 |
| Malin, David H; Alvarado, Candice L; Woodhouse, Katherine S et al. (2002) Passive immunization against nicotine attenuates nicotine discrimination. Life Sci 70:2793-8 |
| Pentel, Paul; Malin, David (2002) A vaccine for nicotine dependence: targeting the drug rather than the brain. Respiration 69:193-7 |
| Malin, D H (2001) Nicotine dependence: studies with a laboratory model. Pharmacol Biochem Behav 70:551-9 |
