Active Immunization against Nicotine Suppresses Nicotine-Induced Dopamine Release in the Rat Nucleus accumbens Shell

Abstract

Background: Tobacco smoking is the largest preventable cause of morbidity and premature mortality in the world. Although its medical consequences are well documented, 20–50% of the population even in developed countries remain tobacco smokers. The drugs presently used in smoking cessation have limited efficiency and, therefore, there is a need for alternative and improved treatments. One novel approach in this regard may be provided by immunization against nicotine. Objective: The present study in male Wistar rats investigated if active immunization with a novel nicotine immunogen, IP18-KLH, may generate nicotine-selective antibodies and, furthermore, whether this treatment might prevent nicotine from exerting its stimulating effect on the mesolimbic, dopaminergic reward system in the brain. Methods: Enzyme-linked immunosorbent assay (ELISA) was used to determine the titer of nicotine antibodies in plasma after immunization with IP18-KLH in Freund’s adjuvant. Competitive ELISA was used to assess the selectivity of the antibodies. Finally, we used in vivo voltammetry to investigate whether active immunization with IP18-KLH could prevent nicotine-induced dopamine release in the shell of nucleus accumbens (NAC_shell). Results: The present study shows that active immunization with IP18-KLH generates antibodies that are highly selective for nicotine. Furthermore, immunization with IP18-KLH prevented the nicotine-induced increase in dopamine release in the NAC_shell, a biochemical correlate to the rewarding properties of nicotine. Conclusions: Active immunization with IP18-KLH prevents a central effect of nicotine that is considered critical for the induction of nicotine dependence. Consequently, active immunization may provide long-term protection against initiation of tobacco dependence, an effect that may prove particularly advantageous in relapse prevention.

A therapeutic vaccine for nicotine dependence: preclinical efficacy, and phase I safety and immunogenicity

“…Coupling haptens to protein carriers typically enhances their immunogenicity. Nicotine conjugates have been successfully used to vaccinate against nicotine [11][12][13][14][15]. Vaccine efficacy in animal models was demonstrated in several different ways.…”

“…Correspondingly, nicotine concentrations in the brain were lower [11,12,14,15]. The effect on the reward system in brain was demonstrated by suppression of nicotine-induced dopamine release in brains of vaccinated rats [13]. In two animal models, the potential to prevent relapse was investigated: anti-nicotine antibodies prevented the alleviation of abstinence syndromes by nicotine [16] and prevented reinstatement of nicotine-seeking behavior in vaccinated rats [17].…”

Avances en el desarrollo de productos biológicos para el tratamiento de la adicción a las drogas y las sobredosis

“…This is a nicotine immunoconjugate IP18-KLH that prevents the access of nicotine to the brain and has demonstrated to reduce the increase in dopamine output in the nucleus accumbens induced by nicotine as well as the reinstatement of nicotine-seeking behavior in rats. It has also been found that IP18-KLH not only did not precipitate but also ameliorate nicotine withdrawal in rats (de Villiers et al, 2010;de Villiers et al, 2002). Therefore, individuals treated with IP18-KLH may even have milder nicotine withdrawal symptoms when they quit smoking.…”

Ethical and policy issues in using vaccines to treat and prevent cocaine and nicotine dependence

“…In rat models of addiction, antibodies induced to cocaine [7][8][9][10] and nicotine [11,12] substantially reduce the amount of these drugs that reaches the brain [13]. Immunization against cocaine and nicotine attenuates self-administration [7] and suppresses dopamine release in the nucleus accumbens shell [13].…”

“…Immunization against cocaine and nicotine attenuates self-administration [7] and suppresses dopamine release in the nucleus accumbens shell [13].…”