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Comparison of the reinforcing properties of nicotine and cigarette smoke extract in rats.

ABSTRACT: Tobacco dependence is difficult to treat, with the vast majority of those who try to quit relapsing within the first year. Improvements in smoking cessation therapies may be achieved by improving current preclinical research methods. However, most experimental tests in animals use nicotine alone, ignoring the 8000 other constituents found in tobacco smoke. To improve on this model, we have used self-administration to test the reinforcing properties of aqueous cigarette smoke extract (CSE) in rats, made by bubbling cigarette smoke through a saline solution. CSE is more potent than nicotine alone in both the acquisition and maintenance of self-administration, but did not exhibit higher progressive ratio responding. Mecamylamine and varenicline had similar potencies to block nicotine and CSE self-administration, indicating the involvement of nicotinic receptors in CSE reinforcement. Following extinction of responding, reinstatement was triggered by exposing animals to a pharmacological stressor, yohimbine (2.5 mg/kg, i.p.), alone and in combination with cues. Animals that self-administered CSE were significantly more sensitive to stress-induced reinstatement than those that self-administered nicotine. Ligand binding autoradiography studies showed nicotine and CSE to have similar affinities for different nicotinic receptor types. CSE significantly reduced MAO-A and MAO-B activities in vitro, whereas nicotine did not. Although CSE inhibition of MAO-A activity in vitro was found to be partially irreversible, irreversible inhibition was not observed in vivo. These experiments show that CSE is an effective reinforcer acting via nicotinic receptors. Furthermore, it better models MAO inhibition and is more sensitive to stress-induced reinstatement than nicotine alone, which is a potent trigger for relapse in smokers.

SUBMITTER: Costello MR

PROVIDER: S-EPMC4059892 | biostudies-other | 2014 Jul

REPOSITORIES: biostudies-other

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Comparison of the reinforcing properties of nicotine and cigarette smoke extract in rats.

Costello Matthew R MR Reynaga Daisy D DD Mojica Celina Y CY Zaveri Nurulain T NT Belluzzi James D JD Leslie Frances M FM

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20140211 8

Tobacco dependence is difficult to treat, with the vast majority of those who try to quit relapsing within the first year. Improvements in smoking cessation therapies may be achieved by improving current preclinical research methods. However, most experimental tests in animals use nicotine alone, ignoring the 8000 other constituents found in tobacco smoke. To improve on this model, we have used self-administration to test the reinforcing properties of aqueous cigarette smoke extract (CSE) in rat ...[more]

PMID: 24513971

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Project description:Background: We found previously that ursolic acid (UA) administration could alleviate cigarette smoke-induced emphysema in rats partly through the unfolded protein response (UPR) PERK-CHOP and Nrf2 pathways, thus alleviating endoplasmic reticulum stress (ERS)-associated oxidative stress and cell apoptosis. We hypothesized that other UPR pathways may play similar roles in cigarette smoke extract (CSE)-induced emphysema. So, we sought to investigate the dynamic changes and effects of UPR and the downstream apoptotic pathways. Further, we investigated whether UA could alleviate CSE-induced emphysema and airway remodelling in rats, whether and when it exerts its effects through UPR pathways as well as Smads pathways. Methods: One hundred eight Sprague Dawley (SD) rats were randomly divided into three groups: Sham group, CSE group, and UA group, and each group was further divided into three subgroups, administered CSE (vehicle) for 2, 3, or 4 weeks; each subgroup had 12 rats. We examined pathological changes, analyzed the three UPR signaling pathways and subsequent ERS, intrinsic and extrinsic apoptotic pathway indicators, as well as activation of Smad2,3 molecules in rat lungs. Results: Exposure to CSE for 3 or 4 weeks could apparently induce emphysema and airway remodeling in rats, including gross and microscopic changes, alteration of mean alveolar number (MAN), mean linear intercept (MLI), and mean airway thickness in lung tissue sections. UA intervention could significantly alleviate CSE-induced emphysema and airway remodeling in rats. UA exerted its effects through ameliorating apoptosis by down regulating UPR signalling pathways and subsequent apoptosis pathways, as well as, downregulating p-Smad2 and p-Smad3 molecules. Conclusions: UA attenuated CSE-induced emphysema and airway remodeling, exerting its effects partly through regulation of three UPR pathways, amelioration downstream apoptotic pathways, and alleviating activation of Smad2 and Smad3.

Project description:IntroductionWaterpipe use remains popular among youth with the availability of flavored shisha tobacco being one of the main drivers of waterpipe use. Although waterpipe mainstream toxicant emissions are well understood, less is known about the carryover of flavorants such as vanillin, benzaldehyde, and eugenol. In this study, flavored waterpipe tobacco was analyzed for flavorants and nicotine, and subsequent carryover to mainstream smoke.MethodsFlavorants vanillin, benzaldehyde, and eugenol, and nicotine were quantified in vanilla-, cherry-, and cinnamon-flavored shisha tobacco by gas chromatography/flame ionization detector and subsequently in waterpipe mainstream smoke generated by a smoking machine. The setup allowed for sampling before and after the water-filtration step.ResultsFlavorant and nicotine content in smoke was reduced 3- to 10-fold and 1.4- to 3.1-fold, respectively, due to water filtration. Per-puff content of filtered waterpipe mainstream smoke ranged from 13 to 46 µg/puff for nicotine and from 6 to 55 µg/puff for flavorants.ConclusionsAlthough water filtration reduced flavor and nicotine content in waterpipe mainstream smoke, the detected flavorant concentrations were similar or higher to those previously reported in e-cigarette aerosol. Therefore, users could be drawn to waterpipes due to similar flavor appeal as popular e-cigarette products. Absolute nicotine content of waterpipe smoke was lower than in e-cigarette aerosol, but the differential use patterns of waterpipe (>100 puffs/session) and e-cigarette (mostly <10 puffs/session, multiple session throughout the day) probably result in higher flavorant and nicotine exposure during a waterpipe session. Strategies to reduce youth introduction and exposure to nicotine via waterpipe use may consider similar flavor restrictions as those for e-cigarettes.ImplicationsAlthough waterpipe mainstream smoke is well characterized for toxicants content, little is known about carryover of molecules relevant for appeal and addiction: flavorants and nicotine. This study shows that flavorant content of waterpipe mainstream smoke is comparable or higher than e-cigarette aerosol flavorant content. Regulatory action to address tobacco use behaviors targeting the availability of flavors should also include other tobacco products such as flavored shisha tobacco.

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Comparison of the reinforcing properties of nicotine and cigarette smoke extract in rats.

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Comparison of the reinforcing properties of nicotine and cigarette smoke extract in rats.

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