title: Effect of Brain CYP2B Inhibition on Brain Nicotine Levels and Nicotine Self-Administration.
abstract: The CYP2B enzyme is expressed in human and rat brain, and metabolizes many CNS-acting drugs. The gene that encodes human CYP2B6 is highly polymorphic, where the variation in brain enzyme levels could result in altered brain drug levels. CYP2B can metabolize nicotine, the main psychoactive ingredient in cigarettes; if altered brain CYP2B activity can influence nicotine brain levels, it could influence nicotine-mediated behaviors. To investigate this, a mechanism-based inhibitor selective for CYP2B, C8-xanthate (20 μg), was administered intracerebroventricularly (ICV) into the brain of rats, and 22 h later, nicotine levels were measured by in vivo microdialysis following nicotine (150 μg/kg intravenous). Brain nicotine levels from 15 to 30 min and the AUC0-45 min were both twofold higher (p<0.05) with C8-xanthate vs vehicle pretreatment; there was no difference in peripheral nicotine levels. Rats were then given ICV pretreatment with C8-xanthate/ASCF and underwent intravenous nicotine self-administration with 3.75-30 μg/kg per infusion dose. C8-xanthate pretreatment increased responding in progressive ratio (15 μg/kg per infusion dose, p<0.05). In a separate cohort, C8-xanthate increased the percentage of rats that acquired self-administration (7.5 μg/kg per infusion dose, p<0.05) from 40% after vehicle pretreatment to 100%, with no difference in peripheral nicotine levels measured at the end of behavior. In a third cohort, C8-xanthate increased the number of sessions required to meet extinction criteria (p<0.05). Together these data demonstrate that the brain CYP2B activity can influence nicotine brain levels and subsequent behaviors independent of hepatic metabolism. This suggests that human smokers with variable CYP2B brain levels could have different nicotine levels and reinforcement, which might have a role in smoking behaviors and dependence.
authors: 1] Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada [2] Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada [3] Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors: Kristine L P
authors: KL
authors: Garcia
authors: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors: Kathy
authors: K
authors: Coen
authors: 1] Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada [2] Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada [3] Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors: Sharon
authors: S
authors: Miksys
authors: 1] Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada [2] Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada [3] Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors: Anh Dzung
authors: AD
authors: Lê
authors: 1] Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada [2] Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada [3] Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors: Rachel F
authors: RF
authors: Tyndale
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003216:Conditioning, Operant / Q000187:drug effects; D003367:Cotinine / Q000097:blood; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005108:Extinction, Psychological / Q000187:drug effects; D007276:Injections, Intraventricular; D008297:Male; D009538:Nicotine / Q000008:administration & dosage* / Q000378:metabolism*; D018722:Nicotinic Agonists / Q000008:administration & dosage* / Q000378:metabolism*; D051381:Rats; D012054:Reinforcement, Psychology; D012646:Self Administration; D013871:Thiones / Q000494:pharmacology; D013997:Time Factors
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D018722:Nicotinic Agonists; D013871:Thiones; D009538:Nicotine; D003367:Cotinine
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