Vaccination against nicotine alters the distribution of nicotine delivered via cigarette smoke inhalation to rats
Graphical abstract
Distribution to brain of nicotine inhaled in cigarette smoke is reduced by vaccination against nicotine.
Introduction
Nicotine vaccines are being studied as a treatment strategy for tobacco dependence. Immunization elicits the production of nicotine-specific antibodies which bind nicotine with high affinity and specificity in serum and extracellular fluid, reduce or slow nicotine distribution to brain, reduce nicotine clearance, and attenuate a wide variety of addiction-like behaviors in rats or mice [1]. Nicotine vaccines have entered clinical trials and several have shown preliminary evidence of efficacy for enhancing smoking cessation rates [2], [3], [4]. Nicotine vaccines were developed through investigation in rodent models of nicotine addiction, and animal work continues in an effort to better understand their mechanism of action and improve their efficacy [5].
Because immunization against nicotine is a pharmacokinetic intervention [1], it is important that animals models used to study its mechanism of action and effects model the key features of nicotine pharmacokinetics in cigarette smokers. Rodent models of nicotine exposure generally consist of nicotine administered intravenously or subcutaneously [6]. At appropriate doses, these modes of nicotine administration produce arterial and venous serum nicotine concentrations similar to those of cigarette smokers [7], [8]. However they differ from the nicotine exposure of cigarette smokers in the route of absorption (inhaled vs. parenteral) and the absence of the thousands of other chemicals that are present in tobacco smoke. Tobacco components such as bicarbonate may influence the rate of nicotine absorption, and lung contains enzymes which contribute to nicotine metabolism [9], [10]. In addition, pulmonary mucosa produces antibody, principally IgA, that could contribute to effects of nicotine vaccines on nicotine disposition. It is unclear to what extent these aspects of nicotine dosing from cigarette smoke inhalation are important in understanding and modeling the use of nicotine vaccines. Inhalation of nicotine from tobacco smoke in humans allows rapid absorption from the lung into left atrial blood and results in a high initial arterial nicotine concentration which is delivered to the brain [11], [12]. In smokers this is produced by discrete puffs of a cigarette inhaled over a 5–10 min period, whereas rat models generally use a single i.v. bolus dose of nicotine equivalent to the dose absorbed from 1 to 2 cigarettes because this dose produces clinically relevant serum nicotine concentrations and maintains behaviors of interest such as nicotine self-administration [6]. Subcutaneous dosing of nicotine results in absorption over 10–20 min but generally utilizes nicotine doses equivalent to 10–20 cigarettes. These models of nicotine dosing appear to model many of the clinical effects of nicotine reasonably well, but clearly differ in key respects from nicotine exposure during cigarette smoking.
Cigarette smoke exposure of rodents has been used widely for studying smoke toxicology [13], [14] but its use to investigate nicotine pharmacokinetics or tobacco addiction has been quite limited [15], [16], [17], [18], [19], and no studies to date have used rodent smoke exposure to investigate pharmacotherapies for tobacco addiction. In the current study rats were exposed to cigarette smoke under well defined conditions modeling the smoking of 1 cigarette over 10 min or the smoking of multiple cigarettes over 2 h, as well to as i.v. nicotine. The effects of a nicotine vaccine on the distribution of nicotine to brain and the retention of nicotine in broncheoalveolar lavage fluid were assessed. Effects of passive administration with a nicotine-specific monoclonal antibody were also studied to clarify the potential role of pulmonary mucosal antibody, since vaccination may stimulate pulmonary mucosal antibody production whereas passive immunization would not.
Section snippets
Animals
Male Holtzman Sprague–Dawley rats (Harlan, Indianapolis, IN) weighing 300–325 g at the time of arrival were housed individually under a 12 h light/dark cycle and were studied during the light (inactive) cycle. Beginning 1 week after arrival, animals were restricted to 18 g/day of food to prevent them from becoming too large for the NSE restraint bottles. Protocols were approved by the Minneapolis Medical Research Foundation Animal Care and Use Committee.
Immunization
The nicotine vaccine used was
10 min smoke NSE
The serum nicotine-specific IgG antibody concentration in rats vaccinated with 3′-AmNic-rEPA was 280 ± 120 μg/ml, comparable to previous studies in rats with this vaccine (Table 1). The serum nicotine concentration in control rats immunized with rEPA alone was 7 ± 1 ng/ml, as intended to approximate the serum nicotine concentration boost produced by the smoking of 1 cigarette. Vaccination resulted in substantial retention of nicotine in serum (210 ± 80 ng/ml) compared to controls (p < 0.001) and a
Discussion
This study used cigarette smoke exposure in an effort to capture some of the features of nicotine delivery to a cigarette smoker that are not provided by parenteral nicotine dosing. Rodent models of cigarette exposure have been used widely to study tobacco smoke toxicology, particularly carcinogenesis [13], [14]. Much less attention has been directed at using smoke exposure systems to study nicotine pharmacology or pharmacokinetics, and most such studies have not measured serum or tissue
Acknowledgments
The 3′-AmNic-rEPA immunogen and rEPA carrier protein were gifts of Nabi Biopharmaceuticals. Internal standard for the nicotine assay was a gift from P Jacob (University of California, San Francisco). Supported by PHS grants DA10714, DA010714-13S1, T32-DA07097, and a Career Development Award from the Minneapolis Medical Research Foundation (MP).
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2016, Toxicology and Applied PharmacologyCitation Excerpt :One possible therapeutic option that applies this concept as a mode of stemming nicotine addiction is the nicotine vaccine. There are currently a number of studies claiming the successful application of a conjugate nicotine vaccine in animals (Hieda et al., 1997, 1999, 2000; Keyler et al., 1999, 2008; Pentel et al., 2000; Pentel and Malin, 2002; Satoskar et al., 2003; de Villiers et al., 2010, 2013; Moreno et al., 2010; Cornish et al., 2011; Pravetoni et al., 2011, 2012; Lockner et al., 2013, 2015; Pryde et al., 2013; Hu et al., 2014; Miller et al., 2014; Zheng et al., 2015). In the majority of these studies, immunogenic carrier proteins are conjugated to nicotine molecules via a linker modification added to nicotine's pyrrolidine ring or pyrodine ring (Keyler et al., 1999).
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2014, Advances in PharmacologyCitation Excerpt :Animal models of nicotine vaccines generally involve the administration of nicotine i.v. or s.c. rather than by inhalation and by itself rather than in combination with the thousands of other chemicals present in tobacco and tobacco smoke. One study showed that a nicotine vaccine was equally effective for blocking nicotine distribution to the brain after a single dose of nicotine administered either i.v. or via inhalation of cigarette smoke (Pravetoni et al., 2011). This validates the pharmacokinetic aspects of the i.v. model but does not address the possible behavioral effects of other compounds in tobacco smoke.