Passive Immunization to treat nicotine dependence in rats.

Abstract

Cigarette smoking is the leading preventable cause of death in the United States, primarily due to nicotine addiction. Currently available medications are only partially effective in increasing smoking cessation, and additional therapies are needed. Immunotherapy is an alternative strategy for attenuating nicotine's addictive effects. Vaccination against nicotine alters nicotine pharmacokinetics and nicotine's behavioral effects in rats. In clinical trials, nicotine vaccines reduce smoking, but efficacy is limited by high variability and low mean serum nicotine-specific antibody (NicAb) levels. Passive immunization is an alternative method of immunization, and can potentially circumvent the limitations of vaccination by allowing control over the dose and timing of NicAb administration. The overall goal of this thesis was to examine the use of passive immunization to treat tobacco addiction. The specific aims were to characterize the efficacy of passive immunization on nicotine pharmacokinetics and nicotine-induced behavior, explore the effects of combining vaccination with passive immunization, and examine a potential adverse effect of passive immunization, the precipitation of withdrawal. Passive immunization with the nicotine-specific monoclonal antibody Nic311 reduced nicotine clearance and steady-state volume of distribution, and prolonged nicotine's elimination half-life, demonstrating the underlying mechanism of immunotherapy efficacy. Nic311 attenuated nicotine-induced locomotor sensitization, and combining Nic311 with vaccination resulted in greater reductions in brain nicotine levels and nicotine-induced locomotor sensitization compared to either immunotherapy alone, demonstrating the behavioral efficacy of Nic311 and suggesting a possible clinical role as a supplement for vaccination. Administration of Nic311 to nicotine-dependent rats substantially reduced brain nicotine levels but did not elicit a nicotine withdrawal syndrome. These findings demonstrate the benefits and safety of passive immunization with Nic311, and point to its potential in treating nicotine addiction.