Ethanol self‐administration and nicotine treatment increase brain levels of CYP 2 D in A frican green monkeys

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.