Zhu, Andy Z.XMuldoon, Pretal P.Tyndale, Rachel F.Damaj, Mohamad Imad2022-09-022022-09-022014-10Bağdaş, D. vd. (2014). "Effects of methoxsalen, a CYP2A5/6 inhibitor, on nicotine dependence behaviors in mice". Neuropharmacology, 85, 67-72.0028-39081873-7064https://doi.org/10.1016/j.neuropharm.2014.05.006https://www.sciencedirect.com/science/article/pii/S0028390814001737http://hdl.handle.net/11452/28441Metabolism 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.eninfo:eu-repo/semantics/openAccessNicotineDependenceMethoxsalenMiceMetabolismCYP2A(4/5)BGS-null mouseSelective inhibitorsSmoking-cessationMetabolite ratio2A6AssociationWithdrawalOxidationNeurosciences & neurologyPharmacology & pharmacyAnimalsAnxietyAryl hydrocarbon hydroxylasesConditioning (psychology)Disease models, animalDose-response relationship, drugEnzyme inhibitorsHyperalgesiaMaleMecamylamineMethoxsalenMice, inbred ICRMotor activityNicotineNicotinic agonistsNicotinic antagonistsRewardSeverity of illness indexSubstance Withdrawal SyndromeTobacco use disorderArticle0003408536000082-s2.0-8490218660867728524859605NeurosciencesPharmacology & pharmacyCytochrome P450 2A6; Nicotine Tartrate; CotinineMethoxsalenNicotineCyp2a5 protein, mouseEnzyme inhibitorMecamylamineNicotineNicotinic agentNicotinic receptor blocking agentUnspecific monooxygenaseAdultAnimal experimentAnimal modelAnxietyArticleConditioned place preference testControlled studyDrug effectEvening dosageHyperalgesiaMaleMorning dosageMouseNonhumanPriority journalRewardSmoking cessationTobacco dependenceAnimalAntagonists and inhibitorsBloodConditioningDisease modelDose responseDrug effectsHyperalgesiaInstitute for Cancer Research mouseMetabolismMotor activityPathophysiologyPhysiologySeverity of illness indexSubstance Withdrawal SyndromeTobacco use disorder