Elsevier

Biochemical Pharmacology

Volume 81, Issue 9, 1 May 2011, Pages 1164-1170
Biochemical Pharmacology

Vaccination against nicotine alters the distribution of nicotine delivered via cigarette smoke inhalation to rats

https://doi.org/10.1016/j.bcp.2011.02.004Get rights and content

Abstract

Preclinical models of nicotine vaccine pharmacology have relied on i.v. or s.c. administration of nicotine. Models using cigarette smoke inhalation might more accurately simulate nicotine exposure in smokers. Nicotine vaccine effects were examined in rats using two cigarette smoke exposure models: a 10 min nose-only exposure (NSE) producing serum nicotine levels equivalent to the nicotine boost from 1 cigarette in a smoker, and a 2 h whole-body exposure (WBE) producing serum nicotine levels similar to those associated with regular mid-day smoking. Vaccination prior to 10 min smoke NSE reduced nicotine distribution to brain by 90%, comparable to its effect on nicotine administered i.v. Vaccination prior to 2 h smoke WBE reduced nicotine distribution to brain by 35%. The nicotine concentration in broncheoalveolar lavage (BAL) fluid obtained after 2 h WBE was increased by 230% in vaccinated rats but was also increased in rats passively immunized with a nicotine-specific monoclonal antibody, and so was likely due to transfer of antibody from serum rather than local production at the pulmonary mucosa. Nicotine-specific IgA was not detectable in BAL fluid, but titers in serum were appreciable at 21–25% of the IgG titer and could contribute to vaccine efficacy. Both vaccination and passive immunization are effective in reducing nicotine distribution to brain in rats when nicotine is delivered via inhaled cigarette smoke. These data validate results previously obtained in rodents for nicotine vaccines using i.v. or s.c. nicotine dosing and provide a quantitative method for studying aspects of nicotine exposure which are unique to cigarette smoke inhalation.

Graphical abstract

Distribution to brain of nicotine inhaled in cigarette smoke is reduced by vaccination against nicotine.

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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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