title: Ethanol self-administration and nicotine treatment increase brain levels of CYP2D in African green monkeys.
abstract: OBJECTIVE
  CYP2D6 metabolizes many centrally acting drugs, neurotoxins and endogenous neurochemicals, and differences in brain levels of CYP2D have been associated with brain function and drug response. Alcohol consumers and smokers have higher levels of CYP2D6 in brain, but not liver, suggesting ethanol and/or nicotine may induce human brain CYP2D6. We investigated the independent and combined effects of chronic ethanol self-administration and nicotine treatment on CYP2D expression in African green monkeys.
  
  
  METHODS
  Forty monkeys were randomized into control, ethanol-only, nicotine-only and ethanol + nicotine groups. Two groups voluntarily self-administered 10% ethanol in sucrose solution for 4 h·day(-1) , whereas two groups consumed sucrose solution on the same schedule. Two groups received daily s.c. injections of 0.5 mg·kg(-1) nicotine in saline bid, whereas two groups were injected with saline on the same schedule.
  
  
  RESULTS
  Both nicotine and ethanol dose-dependently increased CYP2D in brain; brain mRNA was unaffected, and neither drug altered hepatic CYP2D protein or mRNA. The combination of ethanol and nicotine increased brain CYP2D protein levels to a greater extent than either drug alone (1.2-2.2-fold, P < 0.05 among the eight brain regions assessed). Immunohistochemistry revealed the induction of brain CYP2D protein within specific cell types and regions in the treatment groups.
  
  
  CONCLUSIONS
  Ethanol and nicotine increase brain CYP2D protein levels in monkeys, in a region and treatment-specific manner, suggesting that CNS drug responses, neurodegeneration and personality may be affected among people who consume alcohol and/or nicotine.
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health and Departments of Psychiatry, Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
authors.forename: R T
authors.initials: RT
authors.lastname: Miller
authors.forename: S
authors.initials: S
authors.lastname: Miksys
authors.forename: E
authors.initials: E
authors.lastname: Hoffmann
authors.forename: R F
authors.initials: RF
authors.lastname: Tyndale
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis* / Q000235:genetics; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D000431:Ethanol / Q000008:administration & dosage*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D012646:Self Administration
chemical_list: D018722:Nicotinic Agonists; D012333:RNA, Messenger; D000431:Ethanol; D009538:Nicotine; D001189:Aryl Hydrocarbon Hydroxylases
keywords: CYP2D; brain; ethanol; induction; liver; monkey; nicotine