Differential effects of non-nicotine tobacco constituent compounds on nicotine self-administration in rats

Hall, Brandon J.; Wells, Corinne; Allenby, Cheyenne; Lin, Mung Yan; Hao, Ian; Marshall, Lindsey; Rose, Jed E.; Levin, Edward D.

doi:10.1016/j.pbb.2014.02.011

Cited by 51 publications

(45 citation statements)

References 40 publications

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“…17 Myosmine itself has not been evaluated for self-administration; however, myosmine doses of 0.02-2 mg/kg did not affect nicotine self-administration. 18 The present results demonstrate that, while the effects of cotinine and myosmine on locomotor activity are more similar to each other than to those of nicotine, the pharmacological profiles also differ, in that higher doses of myosmine (10-50 mg/kg) produced signs of malaise (e.g., flattened body posture, ptosis) whereas cotinine at doses up to 50 mg/kg did not alter overt behavior.…”

Section: Discussionsupporting

confidence: 52%

“…self-administration procedures, but was not reinforcing itself. [18][19][20] In summary, nicotine, cotinine, myosmine and anatabine produced distinctive patterns of effects on locomotor activity that were timeand dose-dependent. Nicotine and cotinine proved to be the most potent constituents (with lowest effective doses of 0.1 mg/kg) whereas the lowest effective doses of anatabine and myosmine were 1 mg/kg and 10 mg/kg, respectively.…”

Section: Discussionmentioning

confidence: 87%

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Determination of Behaviorally Effective Tobacco Constituent Doses in Rats

Wiley

Marusich

Thomas

et al. 2014

Nicotine & Tobacco Research

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IntroductionTobacco use continues to be the leading preventable cause of premature deaths in the United States, with over 400,000 deaths per year attributed to cigarette smoking. 1 While nicotine is the primary tobacco constituent responsible for addiction, many of the other over 8,400 identified tobacco constituents, 2 including alkaloids, flavor additives, β-carbolines, and monoamine oxidase inhibitors, may also affect use and dependence. 3 Given the sparse knowledge about the in vivo pharmacology of most of these constituents, the objective of this study was to examine the effects on locomotor activity of anatabine and myosmine (two alkaloids that are present in larger quantities in tobacco products, including e-cigarettes; Etter, Zäther, and Svensson 4 ; Jacob et al. 5 ), cotinine (common tobacco constituent and a metabolite of nicotine; Jacob et al. 5 ) and nicotine (for comparison purposes). Nicotine doses (0.1-0.8 mg/kg, subcutaneous [s.c.]) were chosen based upon literature review, which showed that acute doses within this range affected locomotor activity, produced AbstractIntroduction: While nicotine has been established as the primary addictive drug that promotes tobacco use, recent peer-reviewed studies suggest that tobacco smoke contains additional chemical constituents that may have addictive potential. Additional research is necessary to determine the addictive potential of these tobacco constituents individually and in combination with tobacco smoke condensate; however, the behaviorally effective constituent doses necessary to conduct such studies are unclear. The primary objective of this study was to conduct behavioral studies in adult rats to determine the relevant behaviorally effective doses of the tobacco constituents, cotinine, myosmine, and anatabine to be used in future studies assessing the addictive potential of these compounds. Methods: Separate groups of adult male Sprague Dawley rats were treated with vehicle, nicotine, or various doses of cotinine, mysomine, or anatabine. Effects on locomotor activity were measured in 10-min bins for 60 min. Results: Nicotine (0.8 mg/kg) produced a biphasic effect on locomotor activity, with hypoactivity during the first 10 min and hyperactivity at 40-50 min. In contrast, cotinine (0.1 mg/kg) and myosmine (10-50 mg/kg) decreased activity without a later increase. Anatabine significantly increased locomotor activity at 1 mg/kg, but decreased it at 10 mg/kg. Prominent effects on overt behavior were observed at anatabine doses of 10 mg/kg and above. Conclusion: Nicotine, cotinine, myosmine, and anatabine produced distinct time-and dose-dependent patterns of effects on locomotor activity. Results from the study will aid in the selection of relevant doses for future studies assessing the addictive potential of these non-nicotine tobacco constituents.

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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 87%

Determination of Behaviorally Effective Tobacco Constituent Doses in Rats

Wiley

Marusich

Thomas

et al. 2014

Nicotine & Tobacco Research

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“…Catheters were surgically implanted into the right jugular veins of each animal in the manner as previously described (Hall et al , 2014). Briefly, animals were anesthetized with a combination of ketamine (60 mg/kg i.p.)…”

Section: Methodsmentioning

confidence: 99%

Bupropion–varenicline interactions and nicotine self-administration behavior in rats

Hall¹,

Slade²,

Wells³

et al. 2015

Pharmacology Biochemistry and Behavior

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Varenicline and bupropion each have been shown to significantly improve cessation of tobacco addiction in humans. They act through different mechanisms and the question about the potential added efficacy with their combined used has arisen. Preclinical animal models of nicotine addiction can help with the evaluation of this combined approach and what dose combinations of varenicline and bupropion may be useful for enhancing tobacco cessation. In this study, we investigated the interacting dose-effect functions of varenicline and bupropion in a rat model of nicotine self-administration. Young adult female Sprague-Dawley rats were allowed to self-administer nicotine in one-hr sessions under an FR1 reinforcement schedule. Varenicline (0.3, 1. 3 mg/kg) and bupropion (8.33, 25, 75 mg/kg) were administered alone or together 15 min before each session. The vehicle saline was the control. Higher doses of each drug alone reduced nicotine self-administration compared to control with reductions of 62% and 75% with 3 mg/kg varenicline and 75 mg/kg bupropion respectively. Lower dose varenicline which does not by itself reduce nicotine self-administration, significantly augmented bupropion effects. The 0.3 mg/kg varenicline dose combined with the 25 and 75 mg/kg bupropion doses caused greater reductions of nicotine self-administration than either dose of bupropion given alone. However, higher dose varenicline did not have this effect. Lower dose bupropion did not augment varenicline effects. Only the high bupropion dose significantly enhanced the varenicline effect. Likewise, combinding 1 mg/kg varenicline with 75 mg/kg bupropion reduced self-administration to a greater extent than either dose alone. These results demonstrate that combination therapy with varenicline and bupropion may be more beneficial than monotherapy with either drug alone.

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“…Recent studies have shown that nonnicotine components in tobacco are also reinforcing or influence nicotine SA. Anabasine dose dependently increased nicotine SA at 0.02 mg/kg s.c. in rats, whereas both anabasine and anatabine reduced nicotine SA at 2 mg/kg s.c. (Hall et al, 2014). Another non-nicotine tobacco component, norharmane, was behaviorally reinforcing on its own, and these reinforcing effects were additive with those of nicotine (Arnold et al, 2014).…”

Section: Nicotinementioning

confidence: 99%