[Show abstract][Hide abstract] ABSTRACT: Introduction:
A nicotine vaccine could prevent relapse to smoking by hindering blood nicotine from reaching the brain. Niccine® is a nicotine hapten tetanus-toxoid conjugate vaccine. The present study evaluated the clinical efficacy of Niccine for tobacco smoking relapse prevention.
Cigarette smokers (n = 355) aged 25-50 years were enrolled in a randomized, double-blind, parallel group 1-year trial encompassing 16 visits and 16 telephone calls. Niccine 40 μg or placebo was administered on Days 0, 28, 56, 90, 150, and 210. Between Days 56-98, subjects were treated with varenicline to aid cessation, targeted for Day 70. Only individuals abstinent between Days 90-98 (n = 265) were allowed to continue to 1 year (n = 219). Relapse to smoking was defined as >5 cigarettes within 7 days or since the last contact, or smoking on >5 occasions within 7 days or since the last contact.
At 1 year, nonrelapse was 43.3% in the Niccine versus 51.1% in the placebo groups (difference = -7.9%; 95% CI = -20.6% to 4.9%). There was no benefit of Niccine on smoking status at 6 or 9 months, exhaled carbon monoxide levels, time to relapse, abstinence, withdrawal symptoms, or smoking reinforcement. Nicotine antibody levels increased (mean = 1.34 μg/ml; SD = 2.84 μg/ml) in the Niccine group, but were not related to relapse. Adverse events except hypersensitivity and compensatory smoking did not differ between groups.
This nicotine vaccine appeared well tolerated but did not influence trajectories of relapse possibly because of insufficient antibody levels or lack of efficacy of the vaccine concept for relapse prevention.
[Show abstract][Hide abstract] ABSTRACT: The aim of the present study was to synthesise and screen a set of novel nicotine hapten immunogens used for the treatment of nicotine dependence. In the screening process we studied the amount of antibodies generated and their selectivity, using ELISA techniques, and their effects on nicotine-induced dopamine release in the NAC(shell) of the rat, assessed by in vivo voltammetry. We conclude that even small changes such as the linker attachment on the nicotine molecule as well as the structure of the linker may greatly influence the selectivity of the antibodies and the central neurobiological effects of nicotine that are considered critical for its dependence producing properties.
[Show abstract][Hide abstract] ABSTRACT: We recently showed that active immunisation with the nicotine immunoconjugate IP18-KLH reduces the nicotine-induced increase in dopamine (DA) output in the nucleus accumbens (NAC) and prevents reinstatement of nicotine-seeking behaviour in rats. These effects are mediated by altered distribution of nicotine, resulting in reduced amounts of nicotine reaching the brain, thereby interfering with the rewarding properties of the drug. The present study was designed to explore the effect of immunisation against nicotine on mecamylamine-precipitated nicotine withdrawal as assessed by the reduction in DA output in the NAC in rats. Measuring brain reward thresholds and somatic signs of nicotine withdrawal, the effects of immunisation were also tested during chronic nicotine treatment and after its withdrawal. Finally, we examined the effect of immunisation on challenge injections of nicotine on brain reward thresholds after the increases in somatic signs and reward thresholds associated with nicotine withdrawal had dissipated. The results show that immunisation with IP18-KLH prevented the decrease in DA output in the NAC associated with mecamylamine-precipitated nicotine withdrawal. Moreover, immunisation against nicotine did not precipitate a withdrawal syndrome, as measured by brain reward thresholds and somatic signs, in rats chronically exposed to nicotine. Furthermore, the withdrawal syndrome elicited after cessation of chronic nicotine administration was attenuated in immunised rats compared to that of mock-immunised rats. Finally, the lowering in reward thresholds after nicotine challenge injections was attenuated in both naïve and previously nicotine-exposed immunised rats. In conclusion, the present results show that immunisation with IP18-KLH did not precipitate nicotine withdrawal in rats. Thus, immunisation with IP18-KLH may not elicit nicotine withdrawal in smokers either. Furthermore, since the withdrawal syndrome in rats was attenuated by immunisation, the nicotine withdrawal in smokers should not be worsened but may even be ameliorated during a quit attempt.
Archiv für Experimentelle Pathologie und Pharmakologie 12/2005; 372(3):182-94. DOI:10.1007/s00210-005-0019-0 · 2.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We have previously shown that active immunization with the nicotine immunoconjugate IP18-KLH attenuates the reinforcing effects of nicotine, i.e., suppresses the nicotine-induced brain dopamine release and prevents reinstatement of the nicotine-seeking behavior in rats. These effects are thought to be due to an alteration of the kinetics of nicotine distribution by the antibodies, resulting in an attenuated nicotine distribution to the brain. In this study, the distribution of nicotine administered at doses corresponding to those used in our previous studies, was investigated in immunized rats and controls. Male Wistar rats received two immunizations with IP18-KLH in Freund's incomplete adjuvant, 21 days apart, and experiments were performed 7-11 days post-immunization under chloral hydrate anesthesia. Blood samples were collected to determine antibody titer and nicotine selectivity using enzyme-linked immunosorbent assay (ELISA) techniques. The animals received an intravenous nicotine dose and were sacrificed either 3 min or 60 min after nicotine administration. Trunk blood was collected and the brains were removed for analysis of nicotine content. The results showed that immunization against nicotine increases the nicotine concentration in blood and significantly decreases the amount of nicotine that reaches the brain. The present findings thus demonstrate an altered distribution of nicotine after immunization with IP18-KLH. Despite the sustained nicotine binding by the antibodies, the active immunization did not alter the metabolism of nicotine to cotinine, the major nicotine metabolite. In conclusion, the attenuation of the reinforcing effect of nicotine after immunization with IP18-KLH, shown previously, is indeed associated with an altered distribution of nicotine.
Archiv für Experimentelle Pathologie und Pharmakologie 11/2004; 370(4):299-304. DOI:10.1007/s00210-004-0960-3 · 2.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The presently available pharmaceutical aids in smoking cessation possess a rather limited effectiveness. Therefore, we have synthesized a series of immunoconjugates that stimulate the induction of antibodies which may bind nicotine in the blood, thereby preventing it from passing the blood-brain barrier. Thus, the reinforcing action of nicotine in the brain, which is the driving force in tobacco smoking, should be abolished.
The present study was undertaken to test this notion in a long-term relapse model in rats, measuring the reinstatement of nicotine-seeking behavior, following active immunization with IP18-KLH, one of our immunoconjugates.
Male Wistar rats were immunized with a nicotine-KLH conjugate (nicotine immunogen) and Freund's adjuvant after having been trained to meet the criteria of stable nicotine self-administration on a fixed ratio (FR3) schedule. The rats were subsequently extinguished from nicotine self-administration behavior and finally, as extinction was completed, they were exposed to small, priming doses of nicotine, which previously have been shown to reinstate the nicotine-seeking behavior. The antibody titers were measured by ELISA.
It was found that rats with high titers (>1:10,000) of antibodies against nicotine, in contrast to those with low/no nicotine selective antibodies, do not reinstate nicotine self-administration behavior when they are exposed to nicotine.
Our findings indicate that active immunization against nicotine may effectively abolish the reinforcing action of nicotine in brain, an effect which is critical for relapse in nicotine dependence. These data suggest the potential utility of active immunization in smoking cessation programs.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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)).
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.
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.
[Show abstract][Hide abstract] ABSTRACT: The present study was undertaken to characterize the regulation of serotonin (5-HT) efflux and neuronal activity in the dorsal raphe nucleus (DRN) as well as to examine the potential ability of the antipsychotic drug risperidone to interfere with these mechanisms.
By using microdialysis in freely moving rats, it was found that administration of the alpha2 adrenoceptor antagonist idazoxan (0.25 mg/kg, SC), the 5-HT1B/D receptor antagonist GR 127,935 (1.0 mg/kg, SC) and risperidone (0.6 or 2.0 mg/kg, SC) increased 5-HT output in the DRN. Local DRN perfusion with GR 127,935 or risperidone via reversed dialysis (100 or 10-100 microM, respectively) enhanced 5-HT efflux in this area, whereas idazoxan (10-100 microM) failed to affect this parameter. Both systemic administration and reversed DRN dialysis of the D2/3 and 5-HT2A receptor antagonists raclopride (2.0 mg/kg, SC or 10-100 microM) and MDL 100,907 (1.0 mg/kg, SC or 10-100 microM), respectively, were without effect. Intraraphe dialysis of the 5-HT1B/D receptor agonist CP 135,807 (0.2 microM) decreased the efflux of 5-HT in the DRN, an effect which was antagonized by co-administration of either GR 127,935 or risperidone (10 and 3.3 microM, respectively). By using single-cell recording, it was found that administration of GR 127,935 (50-400 microg/kg, IV) decreased, whereas CP 135,807 (2.5-20 microg/kg, IV) increased firing of 5-HT cells in the DRN.
Our findings suggest a regulatory role of local 5-HT1B/D receptors on 5-HT efflux as well as cell firing in the DRN and indicate that risperidone may interfere with the regulation of 5-HT availability in this area primarily via blockade of 5-HT1D receptors.
[Show abstract][Hide abstract] ABSTRACT: Objectives: The present study was undertaken to characterize the regulation of serotonin (5-HT) efflux and neuronal activity in the dorsal
raphe nucleus (DRN) as well as to examine the potential ability of the antipsychotic drug risperidone to interfere with these
mechanisms. Methods and results: By using microdialysis in freely moving rats, it was found that administration of the α2 adrenoceptor antagonist idazoxan (0.25mg/kg, SC), the 5-HT1B/D receptor antagonist GR 127,935 (1.0mg/kg, SC) and risperidone (0.6 or 2.0mg/kg, SC) increased 5-HT output in the DRN. Local
DRN perfusion with GR 127,935 or risperidone via reversed dialysis (100 or 10–100µM, respectively) enhanced 5-HT efflux in
this area, whereas idazoxan (10–100µM) failed to affect this parameter. Both systemic administration and reversed DRN dialysis
of the D2/3 and 5-HT2A receptor antagonists raclopride (2.0mg/kg, SC or 10–100µM) and MDL 100,907 (1.0mg/kg, SC or 10–100µM), respectively,
were without effect. Intraraphe dialysis of the 5-HT1B/D receptor agonist CP 135,807 (0.2µM) decreased the efflux of 5-HT in the DRN, an effect which was antagonized by co-administration
of either GR 127,935 or risperidone (10 and 3.3µM, respectively). By using single-cell recording, it was found that administration
of GR 127,935 (50–400µg/kg, IV) decreased, whereas CP 135,807 (2.5–20µg/kg, IV) increased firing of 5-HT cells in the DRN. Conclusions: Our findings suggest a regulatory role of local 5-HT1B/D receptors on 5-HT efflux as well as cell firing in the DRN and indicate that risperidone may interfere with the regulation
of 5-HT availability in this area primarily via blockade of 5-HT1D receptors.
[Show abstract][Hide abstract] ABSTRACT: 1. The effects of risperidone on brain 5-hydroxytryptamine (5-HT) neuronal activity were investigated using microdialysis in the frontal cortex (FC) or the dorsal raphe nucleus (DRN) as well as single cell recording in the DRN. 2. Systemic administration of risperidone (0.6 and 2.0 mg/kg, s.c.) dose-dependently increased 5-HT output in both the FC and the DRN. 3. Local cortical administration of both risperidone or idazoxan enhanced the 5-HT efflux in the FC, whereas local raphe administration of risperidone but not idazoxan increased the output of 5-HT in the DRN. 4. Systemic administration of risperidone (200 micrograms/kg, i.v.) or the selective alpha 1 adrenoceptor antagonist prazosin (400 micrograms/kg, i.v.) decreased, whereas selective alpha 2 adrenoceptor antagonist idazoxan (20 micrograms/kg, i.v.) increased the 5-HT cell firing in the DRN. 5. Pretreatment with the selective 5-HT1A receptor antagonist WAY 100,635 (5.0 micrograms/kg, i.v.) effectively antagonized the inhibition of 5-HT cells induced by risperidone, but failed to prevent the prazosin-induced decrease in 5-HT cell firing in the DRN. 6. The inhibitory effect of risperidone on 5-HT cell firing in the DRN was significantly attenuated in rats pretreated with the 5-HT depletor PCPA (p-chlorophenylalanine; 300 mg/kg/day i.p. for 3 consecutive days) in comparison with drug naive animals. 7. Consequently, the risperidone-induced increase in 5-HT output in the FC may be related to its alpha 2 adrenoceptor antagonistic action, an effect probably executed at the nerve terminal level, whereas the reduction in 5-HT cell firing by risperidone appears to be associated with increased availability of 5-HT in the somatodendritic region of the neurones leading to an enhanced 5-HT1A autoreceptor activation and, in turn, to inhibition of cell firing.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 08/1998; 22(5):815-34. DOI:10.1016/S0278-5846(98)00042-6 · 3.69 Impact Factor