Research Project
6399489
The overall purpose of this SPIRCAP proposal is to perform late preclinical and initial clinical studies evaluating the potential use of nicotine vaccine as a treatment or preventive measure for nicotine dependence. The goals of this component of the SPIRCAP are to perform studies in rats that will a) confirm the equivalence of the Clinical Lot of vaccine (intended for human use) with previously studied Research Lots of vaccine, and 2) study the pharmacokinetics and behavioral mechanisms of vaccine action in order to better understand its potential uses and limitations. Initial studies have shown that a candidate nicotine vaccine developed by the participants in this SPIRCAP proposal has pharmacokinetic, physiologic and behavioral effects on nicotine action consistent with a potential role for vaccination as an approach to treating nicotine dependence. The current proposal provides additional studies of vaccination in rats, focusing on further pharmacokinetic investigation of nicotine and antibody, and of vaccine effects on nicotine self- administration. Specific hypotheses to be tested are that 1) the Clinical Lot of vaccine (manufactured on a larger scale and using alum as an adjuvant) has similar effects on nicotine distribution to brain as Research Lots of vaccine (which use to Freund's adjuvant), 2) Nicotine distribution to brain is preferentially reduced compared to distribution to other organs, providing an explanation for the efficacy of unexpectedly modest antibody doses in modifying nicotine effects, 3) The pharmacokinetic disposition of nicotine-specific antibody is not altered by the binding of nicotine, so that the continued presence of nicotine in immunized rats will not adversely affect the duration of action of antibody, and 4) Vaccination of rats in which nicotine self-administration has already been established will lead to a reduction of self-administration rather than a compensatory increase. The latter two experiments will lead to a reduction of self- administration rather than a compensatory increase. The latter two experiments are important because the clinical trial described in Dr. Hatsukami's component proposes to vaccination subject while they are still smoking, so that antibody titers are maximal at the time that they quit. Together with complementary studies of the physiologic and behavioral effects of vaccination performed in Dr. Malin's lab, these data will provide assurance that the Clinical Lot of vaccine is suitable for human use, and will provide information regarding the mechanism of action of vaccination that will aid in the design of the proposed and future clinical trials.
