The purpose of this study is to evaluate whether immunization of rats produce nicotine-specific antibodies can block the central nervous system (CNS) effects of nicotine. The long term goal of this work is to explore the use of immunization as an adjunct to smoking cessation. Immunization has been shown to markedly reduce the behavioral effects of heroin or cocaine in animals. Nicotine is an even better candidate for this approach to reducing drug use because it is administered at substantially lower doses than heroin or cocaine, thus requiring far less antibody to modify its effects. Specific hypotheses to be tested are that (1) nicotine-specific antibodies can bind nicotine in serum and reduce nicotine distribution to brain, (2) achievable titers of antibody are sufficient to bind clinically relevant doses of nicotine, and (3) these pharmacokinetic effects lead to a reduction of the CNS effects of nicotine. A stereospecific immunogen will be synthesized and rats will be immunized to produce antibodies to (S)-nicotine which do not cross react with any of its major metabolites. Immunized rats will be challenged with nicotine, both single and repeated doses, and by multiple routes of administration including i.p., s.c., and rapid injection via the jugular vein to simulate the pharmacokinetics of nicotine absorption from the lungs. Locomotor activity and adrenocorticotropin (ACTH) release in response to nicotine will be measured to determine whether immunization is protective. Plasma and brain concentrations of nicotine will be determined to describe the pharmacokinetic basis for the effects of immunization on nicotine's CNS effects. Passive immunization (production of antibodies in chickens for administration to rats) will also be studied. The affinity purified antibody will be administered to rats to determine the effect of antibody titer on the response to nicotine. Together, these data will assess the feasibility of modifying nicotine's effects by immunization, and provide quantitative pharmacokinetic information regarding the feasibility of adapting this approach, alone or in combination with other therapies, for use in humans.
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