Browsing by Author "Tyndale, Rachel F."
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Item Effects of methoxsalen, a CYP2A5/6 inhibitor, on nicotine dependence behaviors in mice(Pergamon-Elsevier, 2014-10) Zhu, Andy Z.X; Muldoon, Pretal P.; Tyndale, Rachel F.; Damaj, Mohamad Imad; Bağdaş, Deniz; Uludağ Üniversitesi/Tıp Fakültesi/Deney Hayvanları Yetiştirme ve Araştırma Birimi.; 15062425700Metabolism of nicotine to inactive cotinine by hepatic enzyme CYP2A6 is the principal pathway by which active nicotine is removed from circulation. We therefore hypothesized that inhibition of mouse CYP2A5, the ortolog of human CYP2A6, by methoxsalen (8-methoxypsoralen) alter dependence-related behaviors of nicotine in the mouse. Conditioned place preference (CPP) test was used to assess the appetitive reward-like properties and precipitated nicotine withdrawal to assess physical (somatic and hyperalgesia) and affective (anxiety-related behaviors) measures. The nicotine plasma levels were also measured with or without methoxsalen pretreatment. Methoxsalen (15 and 30 mg/kg, intraperitoneally) pretreatment enhanced nicotine-induced preference in mice (p < 0.05). However, there was a lack of enhancement of nicotine in the CPP test after the highest dose of the CYP-2A5 inhibitor. Similarly to the CPP results, repeated administration of methoxsalen increased the intensity of mecamylamine-precipitated withdrawal signs. The potentiation of nicotine preference and withdrawal intensity by methoxsalen was accompanied by significant increase in nicotine plasma levels in mice (p < 0.05). Finally, methoxsalen enhanced the ability of a very low dose of nicotine (0.05 mg/kg) to reverse withdrawal signs in mice undergoing spontaneous withdrawal after chronic nicotine infusion (p < 0.05). In conclusion, inhibition of nicotine metabolism by methoxsalen alters the behavioral effects of nicotine in the mouse. Combining CYP2A6 inhibitors with low dose nicotine replacement therapies may have a beneficial role in smoking cessation because it will decrease the drug elimination rate and maintain plasma and brain nicotine levels.Item Impact of menthol on oral nicotine consumption in female and male sprague dawley rats(Oxford University Press, 2019-02-05) Bağdaş, Deniz; Gül, Zülfiye; Scott, Michael M.; Tyndale, Rachel F.; Damaj, M. Imad; Cam, Betül; Büyükuysal, Levent; Gürün, Mine Sibel; Bursa Uludağ Üniversitesi/Tıp Fakültesi/Farmakoloji Anabilim Dalı.; AAH-1657-2021; CGO-3719-2022; DVX-8040-2022; 56427863700; 6602686612; 55664349700Introduction: One of the preferable flavors in oral nicotine delivery systems is menthol which masks the harshness of tobacco. However, possible interactions between oral menthol and nicotine on intake and preference remain unclear. Therefore, we aimed to determine the impact of menthol on oral nicotine consumption. Methods: Adult Sprague Dawley female and male rats (n = 8 per group) were given a choice of water or drug solution by using two-bottle free choice paradigm for 2 weeks: vehicle (5% ethanol), nicotine (20 mg/L), menthol (1 g/L) and mentholated nicotine groups. At the end of the study, plasma nicotine levels were determined. Results: When rats were given a choice of nicotine or water, nicotine intake was similar between female and male rats. Menthol addition to nicotine solution significantly increased nicotine intake and preference in male but not female rats without a considerable effect on total fluid intake and body weight change in either sex. The average nicotine intake in male rats was 0.5 +/- 0.05 and 1.4 +/- 0.12 mg/kg/day for nicotine and menthol-nicotine combination (p <.05), respectively. The average nicotine intake in female rats was 0.6 +/- 0.05 and 0.6 +/- 0.03 mg/kg/day for nicotine and mentholnicotine combination (p >.05), respectively. Plasma nicotine levels were not significantly different between the groups in either male (nicotine group: 20.8 +/- 4.9, mentholated nicotine group: 31.9 +/- 3.2 ng/mL) or female (nicotine group: 24.0 +/- 3.3, mentholated nicotine group: 17.8 +/- 2.9 ng/mL) rats (p >.05). Conclusions: Menthol increases oral nicotine consumption in male, but not female, rats.