Active immunization against nicotine dependence

Sammanfattning: Tobacco smoking is the largest preventable cause of morbidity and premature mortality in the world. Although its medical consequences are well documented, 20-45% of the adult population in the European countries remains tobacco smokers. The drugs presently used in smoking cessation have limited efficiency and, therefore, there is a need for alternative and improved treatments. A novel type of drug in this regard may be provided by using active immunization against nicotine, i.e. nicotine vaccines. The rationale is to generate endogenous anti-nicotine antibodies that bind nicotine in the blood, thereby preventing it from reaching the brain where it exerts its reinforcing effects. Since nicotine is a small molecule, unable to elicit an immune response, it has to be coupled to a carrier protein via a linker. In this thesis a series of novel nicotine immunogens, including structurally different linkers coupled to the 5- or 6-position of the nicotine molecule and conjugated to a carrier protein, were studied. The amounts of antibodies generated and their selectivity were assessed by ELISA techniques, and all immunogens generated anti-nicotine antibodies that recognized (S)-nicotine or nornicotine better than the other nicotine metabolites tested. In addition, no cross-reactivity to endogenous transmitters was detected. In vivo voltammetry was used to assess the nicotine-induced increase in dopamine release in the shell region of the nucleus accumbens, a neurochemical correlate to nicotine s rewarding properties, and our work revealed that this effect of nicotine was differentially affected depending on both the immunogen studied and the selectivity of the antibodies. The nicotine immunogen IP18-KLH, showing a favorable antibody selectivity profile, prevented the nicotine-induced dopamine release and, likewise, the reinstatement of nicotine-seeking behavior in previously self-administering rats. These effects of the immunization with IP18-KLH were found to be associated with an altered distribution of nicotine, resulting in elevated nicotine levels in serum, due to antibody binding, and consequently a retarded nicotine distribution to the brain. Taken together our results provide substantial preclinical support for the potential utility of nicotine vaccines in the treatment of nicotine dependence, notably relapse prevention.