Novel pharmacological treatment alternatives for nicotine dependence

Abstract: Smoking has been identified as the single largest preventable cause of morbidity and premature death in the developed world. Despite the well known health risks associated with smoking the number of smokers are still rising globally. Available aids in smoking cessation have only limited effectiveness and, therefore, there is a great need for improved treatment in this area. The present set of studies analysed the effects of two novel potential treatment alternatives for smoking cessation; active immunisation against nicotine with the nicotine immunoconjugate IP18-KLH and the dopamine stabiliser (-)-DS121. The aim of the present thesis was to evaluate the effect of these treatments on several aspects of nicotine dependence. First we evaluated their actions on acute effects of nicotine in brain. An increase in dopamine (DA) output is observed in the nucleus accumbens (NAC) following acute administration of most dependenceproducing drugs, including nicotine. This effect has been shown to be critically involved in the reinforcing effect of the drugs, and it is presumed to be important for the acquisition of dependence. Using in vivo voltammetry and in vivo microdialysis the effects, of these treatments on the nicotine-induced increase in DA output in the NAC were examined. Active immuniation with IP18-KLH potently blocked the nicotine-induced increase in DA output in the NAC. The effect of (-)-DS121 was less pronounced showing a significant effect only on DOPAC output. The effect of active immunisation with IP18-KLH on acute injections of nicotine was further evaluated measuring reward thresholds, using intracranial self-stimulation (ICSS) in both nicotine naïve- and previously nicotine-exposed animals. The results show that the facilitating effect of nicotine on reward thresholds was attenuated by active immunisation with IP18-KLH. Measuring reward thresholds we also observed that active immunisation with IP18-KLH does not precipitate nicotine withdrawal, as measured by a lack of increase in reward thresholds during continuous nicotine administration. The effects of the two treatments on different aspects of nicotine withdrawal were also studied. A decrease in DA output in the NAC is observed during precipitated nicotine withdrawal, as well as an increase in somatic signs. Furthermore, nicotine withdrawal is associated with an increase in reward thresholds. During withdrawal we measured DA output in the NAC using in vivo microdialysis and, furthermore, assessed somatic signs. The effect of active immunisation with IP18-KLH on nicotine withdrawal was also evaluated measuring reward thresholds. These measures reflect different aspects of the withdrawal reaction, which are considered to contribute to abstinence symptoms experienced during a quit attempt and to promote early relapse. We observed that both active immunisation with IP18-KLH or treatment with (-)-DS121 attenuated the decrease in DA output in the NAC following precipitated nicotine withdrawal and, furthermore, attenuated the increase in somatic abstinence signs dining precipitated (-)-DS121), or spontaneous (active immunisation), withdrawal. Active immunisation with IP18-KLH was furthermore shown to attenuate the increase in reward thresholds during spontaneous withdrawal. Finally, we evaluated the effect of active immunisation with IP18-KLH on the nicotine-induced reinstatement of nicotineseeking behaviour. This experiment was designed to imitate the situation of drug-induced relapse. Long-term relapse prevention has been pointed out as the major obstacle to overcome in smoking cessation treatment. Our results show that active immunisation with IP18-KLH effectively prevents reinstatement of nicotine-seeking behaviour following administration of a small priming doses of nicotine. In summary, the results from the present thesis provide evidence that both active immunisation against nicotine and the DA stabiliser (-)-DS121 may be effective as treatments for smoking cessation. Our data indicate that active immunisation with IP18-KLH attenuates the acute rewarding effects of nicotine, that the immunisation does not precipitate withdrawal by itself, that it may attenuate nicotine withdrawal and, most significantly that it prevents reinstatement in nicotineseeking behaviour in an experimental relapse model. Furthermore, our results indicate that the dopamine stabiliser (-)DS121 may be effective in attenuating the nicotine withdrawal reaction.