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Ethanol self‐administration and nicotine treatment increase brain levels of CYP 2 D in A frican green monkeys
Author(s) -
Miller R T,
Miksys S,
Hoffmann E,
Tyndale R F
Publication year - 2014
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12652
Subject(s) - nicotine , ethanol , pharmacology , self administration , saline , chemistry , alkaloid , endocrinology , medicine , biochemistry , stereochemistry
Background and Purpose CYP 2 D 6 metabolizes many centrally acting drugs, neurotoxins and endogenous neurochemicals, and differences in brain levels of CYP 2 D have been associated with brain function and drug response. Alcohol consumers and smokers have higher levels of CYP 2 D 6 in brain, but not liver, suggesting ethanol and/or nicotine may induce human brain CYP 2 D 6. We investigated the independent and combined effects of chronic ethanol self‐administration and nicotine treatment on CYP 2 D expression in A frican green monkeys. Experimental Approach 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. Key Results Both nicotine and ethanol dose‐dependently increased CYP 2 D in brain; brain mRNA was unaffected, and neither drug altered hepatic CYP 2 D protein or mRNA . The combination of ethanol and nicotine increased brain CYP 2 D 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 CYP 2 D protein within specific cell types and regions in the treatment groups. Conclusions and Implications Ethanol and nicotine increase brain CYP 2 D 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.