title: Effects of methoxsalen, a CYP2A5/6 inhibitor, on nicotine dependence behaviors in mice.
abstract: Metabolism 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.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298-0613, USA; Experimental Animals Breeding and Research Center, Faculty of Medicine, Uludag University, Bursa 16059, Turkey. Electronic address: dbagdas@vcu.edu.
authors.forename: Deniz
authors.initials: D
authors.lastname: Bagdas
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298-0613, USA.
authors.forename: Pretal P
authors.initials: PP
authors.lastname: Muldoon
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Department of Pharmacology and Toxicology, and Psychiatry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Andy Z X
authors.initials: AZ
authors.lastname: Zhu
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Department of Pharmacology and Toxicology, and Psychiatry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Rachel F
authors.initials: RF
authors.lastname: Tyndale
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298-0613, USA.
authors.forename: M Imad
authors.initials: MI
authors.lastname: Damaj
mesh_terms: D000818:Animals; D001007:Anxiety / Q000188:drug therapy / Q000503:physiopathology; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D000072467:Cytochrome P450 Family 2; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D008730:Methoxsalen / Q000494:pharmacology*; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009538:Nicotine / Q000097:blood / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000097:blood / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D012201:Reward; D012720:Severity of Illness Index; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy* / Q000503:physiopathology; D014029:Tobacco Use Disorder / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D004791:Enzyme Inhibitors; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D008464:Mecamylamine; D009538:Nicotine; D001189:Aryl Hydrocarbon Hydroxylases; C585520:Cyp2a5 protein, mouse; D000072467:Cytochrome P450 Family 2; D008730:Methoxsalen
keywords: Dependence; Metabolism; Methoxsalen; Mice; Nicotine