Active Immunization against Nicotine Prevents Reinstatement of Nicotine-Seeking Behavior in Rats

Lindblom, Nina; Villiers, Sabina H. L. de; Kalayanov, G. D.; Gordon, Sandra; Johansson, Anette M.; Svensson, Torgny H.

doi:10.1159/000063629

Cited by 97 publications

(57 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Reinstatement is evident when the priming infusion of nicotine produces a signi¿ cant increase in responding on the lever that produced nicotine infusions during training. In one study, 42 rats were vaccinated with nicotine or control immunogen during the extinction period prior to the reinstatement test. While control rats exhibited a signi¿ cant increase in responding following a low priming dose of nicotine, vaccinated rats did not.…”

Section: Reinforcing Effectsmentioning

confidence: 99%

Current status of immunologic approaches to treating tobacco dependence: Vaccines and nicotine-specific antibodies

LeSage

Keyler

Pentel

2006

AAPS J

View full text Add to dashboard Cite

In contrast to current pharmacotherapies, immunologic approaches to treating tobacco dependence target the drug itself rather than the brain. This approach involves the use of nicotine-speci¿ c antibodies that bind nicotine in serum, resulting in a decrease in nicotine distribution to the brain and an increase in nicotine's elimination half-life. This review summarizes the literature examining the effects of immunologic interventions on the pharmacokinetics and behavioral effects of nicotine in animal models, as well as recent phase I and II clinical trials in humans. Studies using various vaccines and nicotine-speci¿ c antibodies in rodents have shown that immunization can signi¿ cantly reduce the behavioral effects of nicotine that are relevant to tobacco dependence (eg, nicotine self-administration). These ¿ ndings provide proof of principle that immunologic interventions could have utility in the treatment of tobacco dependence. Thus far, phase I clinical trials of nicotine vaccines have not produced any serious adverse events in humans and have produced dose-dependent increases in serum antibody levels. Although preliminary data from these small trials suggest that vaccination can facilitate abstinence from tobacco use, more advance trials are needed. By acting outside the nervous system, immunologic approaches are less likely to produce the adverse side effects associated with current medications. In addition, the unique mechanism of action of immunotherapy makes it particularly suitable for combination with other pharmacological approaches. Taken together, the work completed to date provides substantial evidence that immunologic interventions could play an important role in future treatment strategies for tobacco dependence.

show abstract

Section: Reinforcing Effectsmentioning

confidence: 99%

Current status of immunologic approaches to treating tobacco dependence: Vaccines and nicotine-specific antibodies

LeSage

Keyler

Pentel

2006

AAPS J

View full text Add to dashboard Cite

show abstract

“…Until it is overcome, conclusions about the model's value to patients, or about its lack thereof, are premature. Table 1 Preclinical studies of reinstatement in rats Blocked by Naltrexone (opioid antagonist) Nicotine antibodies (Lindblom et al 2002) ABT-431 (D 1 agonist) (Self et al 2000) Flupenthixol (DA antagonist) (Shaham and Stewart 1996) Naltrindole (δ-opioid antagonist) (Ciccocioppo et al, 2002) Baclofen (GABA B agonist) (Campbell et al 1999) Haloperidol (D 2 antagonist) (Ettenberg et al 1996) Buprenorphine (opioid partial agonist) (Comer et al, 1993) Naltrexone (opioid antagonist) (Shaham and Stewart, 1996) Eticlopride (D 1 antagonist) (Khroyan et al 2000) Raclopride (D 2 antagonist) (Shaham and Stewart 1996) Flupenthixol (DA antagonist) (Khroyan et al 2000) SCH 23390 (D 1 antagonist) (Shaham and Stewart 1996) Nemonapride (D 1 antagonist) (Khroyan et al 2000) Ro 60-0175 (5-HT 2C agonist) (Grottick et al 2000) SCH 23390 (D 1 antagonist) (Norman et al 1999) SCH 39166 (ecopipam) (D 1 antagonist) (Khroyan et al 2000) SKF 81297, 83959, 82958, or 38393 (D 1 agonists or partial agonists) (Self et al 1996;Khroyan et al 2000) SR 141617A (cannabinoid antagonist) …”

Section: Resultsmentioning

confidence: 99%

The reinstatement model and relapse prevention: a clinical perspective

2003

View full text Add to dashboard Cite

Objectives-This commentary assesses the degree to which the reinstatement model is homologous to the human experience of relapse.Results-A review of the literature suggests that the relationship is less clear than is often assumed, largely due to a lack of prospective data on the precipitants and process of relapse (especially relapse to heroin or cocaine abuse). However, reinstatement does not need to resemble relapse to have immediate clinical value; predictive validity as a medication screen would be sufficient. Whether the model has predictive validity is unknown, because, to date, very few clinical trials have tested medications that are effective in the reinstatement model, and even fewer have used designs comparable to those of reinstatement experiments. A clinical trial comparable to a reinstatement experiment would enroll participants who are already abstinent, and its main outcome measure would be propensity to undergo a specific type of relapse (e.g., relapse induced by stress or cues).Conclusions-Until clinical and preclinical work are more comparable, criticisms of the reinstatement model's presumed shortcomings are premature.The reinstatement model has generated a body of preclinical data that grows increasingly substantial and impressive (Shaham et al. 2003). Yet opinions remain divided about its relation to clinical realities (Marlatt 1996;Bergman and Katz 1998). In this commentary, we address the issues of whether reinstatement resembles relapse, whether it can be useful without resembling relapse, and why neither of those questions can yet be answered satisfactorily. We have drawn on clinical literature and on our own experiences working with substance abusers. Does reinstatement resemble relapse? MaybeIn most published discussions of the reinstatement model, attention is drawn to the fact that the most widely studied precipitants of reinstatement in rats (drug priming, drug-associated cues, and stress) are provocatively similar to the precipitants of relapse in humans. This is typically taken as a point of commonality between the reinstatement model and the real-life experiences of recovered addicts. It is tempting to agree without further consideration; the assertion that priming, cues, and stress precipitate relapse is intuitively appealing and seems to accord with clinical experience. But how strong is the evidence that most relapses are precipitated by any of those three factors?No definitive answer can be found in the clinical literature. Relapse is usually described retrospectively, with weeks or months intervening between the event and its recollection. This leaves ample time for the introduction of recall bias and the formation of post hoc explanations for the reporter's behavior. As an only slightly tangential illustration of the problem, consider the intuitively plausible prediction that abused children are at increased risk for later addiction. The prediction is confirmed when adult addicts are asked retrospectively about their childhoods -but not when abused and nonabused c...

show abstract

“…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]. Furthermore, vaccination also attenuated nicotine's peripheral effects on locomotor activity and blood pressure [12,16].…”

Section: Introductionmentioning

confidence: 99%

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

Maurer¹,

Jennings²,

Willers³

et al. 2005

Eur. J. Immunol.

258

198

View full text Add to dashboard Cite

Nicotine is the principal addictive component in tobacco, and following uptake acts in the central nervous system. The smoking-cessation efforts of most smokers fail because a single slip often delivers sufficient nicotine to the brain to reinstate the drug-seeking behaviour. Blocking nicotine from entering the brain by induction of specific antibodies may be an effective means to prevent such relapses. The hapten nicotine was coupled to virus-like particles (VLP) formed by the coat protein of the bacteriophage Qb. In preclinical experiments, this Nicotine-Qb VLP (NicQb) vaccine induced strong antibody responses. After intravenous nicotine challenge, vaccinated mice exhibited strongly reduced nicotine levels in the brain compared with control mice. In a phase I study, 32 healthy non-smokers were immunized with NicQb. The vaccine was safe and welltolerated. All volunteers who received NicQb showed nicotine-specific IgM antibodies at day 7 and nicotine-specific IgG antibodies at day 14. Antibody levels could be boosted by a second injection or the addition of Alum as an adjuvant and the antibodies had a high affinity for nicotine. These data suggest that antibodies induced by NicQb may prevent relapses by sequestering nicotine in the blood of immunized smokers.

show abstract

Active Immunization against Nicotine Prevents Reinstatement of Nicotine-Seeking Behavior in Rats

Cited by 97 publications

References 19 publications

Current status of immunologic approaches to treating tobacco dependence: Vaccines and nicotine-specific antibodies

Current status of immunologic approaches to treating tobacco dependence: Vaccines and nicotine-specific antibodies

The reinstatement model and relapse prevention: a clinical perspective

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

Contact Info

Product

Resources

About