The aim of this study is to evaluate the effects of a nicotine vaccine on nicotine pharmacokinetics and nicotine-induced behaviors in rats. The long-term goal of this work is to study the therapeutic potential of vaccination as a medication for the treatment or prevention of nicotine dependence. Previous work has shown that a nicotine vaccine can elicit high titers of nicotine-specific antibodies in rats, markedly reduce the distribution of nicotine to brain, reduce the pressor effect and prevent locomotor stimulation from a single dose of nicotine. The proposed study will extend these observations by examining the effects of immunization on the pharmacokinetics of repeated daily doses of nicotine, and on behavioral models of nicotine dependence. Strategies for enhancing the efficacy of immunization will also be explored. Hypotheses to be tested include: 1) Immunization reduces the distribution to brain of daily nicotine doses which simulate regular cigarette smoking. Parallel experiments will evaluate the effects of vaccination on nicotine pharmacokinetic parameters (elimination half-life, clearance) during chronic nicotine dosing. These experiments will help to assess the extent to which nicotine-specific antibody becomes saturated by nicotine with repeated nicotine dosing and the quantitative limits on its efficacy. 2) Immunization attenuates the acquisition, maintenance and reinstatement of nicotine self-administration. These experiments will assess both the efficacy of immunization and whether it is best suited to preventing the initiation of tobacco dependence, assisting in the cessation of use, or in preventing relapse. 3) Immunization prevents the development of nicotine dependence, as measured by signs of withdrawal after the termination of nicotine dosing. This experiment will complement the nicotine self- administration studies by providing a measure of whether immunization attenuates the negative effects of nicotine that reinforce smoking. 4) The efficacy of immunization can be enhanced by the concurrent use of the nicotinic antagonists mecamylamine or dihydro-beta-erythroidine (DHbetaE). Because they antagonize the actions of nicotine by different mechanisms, immunization and receptor antagonists should have additive blocking effects. 5) Immunization against nicotine can be accomplished even during concomitant nicotine administration. This would expand the clinical settings in which vaccination could be used. Together, these studies will help to understand the mechanisms and quantitative relationships underlying the effects of immunization on the actions of nicotine, and begin to delineate the clinical settings in which therapeutic efficacy could be anticipated.
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