The Effect of Altering Brain CYP2B Activity on Nicotine Self-administration Behaviour and Nicotine Levels in the Brain

Cytochrome P450 (CYP) enzymes play an important role in drug metabolism. While CYPs are abundantly expressed in the liver, where CYP-mediated drug metabolism typically occurs, these enzymes are also expressed in other tissues such as the brain. Local brain drug metabolism can influence the response to drugs that act within the brain. The CYP subfamily 2B (CYP2B) is expressed in the brain and is responsible for metabolizing many central nervous system (CNS)-acting drugs including nicotine, the main psychoactive ingredient in cigarettes. Genetic variation in human CYP2B6 is associated with greater conversion to nicotine dependence and risk of relapse in smokers without influencing peripheral nicotine metabolism. This suggests that local brain nicotine metabolism could influence nicotine levels that in turn mediate nicotine reinforcement and resulting behaviours. The role of brain CYP2B activity in nicotine reinforcement was investigated by injecting a pharmacological CYP2B inhibitor into the brain of rats that then underwent nicotine self-administration (NSA), which models smoking behaviour. Inhibitor-treatment increased NSA acquisition, motivation to obtain nicotine and the number of sessions required to extinguish behaviour, suggesting that inhibiting brain CYP2B activity can augment nicotine-reinforced behaviour. The effect of brain CYP2B inhibition on brain nicotine levels following a nicotine injection was then investigated using in vivo microdialysis. Inhibitor treatment increased peak brain nicotine levels and nicotine levels within 0-45 minutes post-injection compared to vehicle, suggesting that inhibiting brain CYP2B activity reduced nicotine metabolism, resulting in higher brain nicotine levels. Inducing brain CYP2B, by a paradigm that increases CYP2B protein in the brain but not the liver, reduced brain nicotine levels within 15-45 minutes post-injection, suggesting that induction increased brain CYP2B activity and nicotine metabolism. These findings demonstrate that altering brain CYP2B activity can influence brain nicotine levels and that inhibiting brain CYP2B, which increases nicotine levels, may increase nicotine's reinforcing effect consistent with the behaviours in NSA. This is also consistent with the behavioural differences associated with genetic variation in CYP2B6, suggesting that altered brain CYP2B activity may influence smoking behaviour. Thus, these findings provide evidence that brain CYPs can influence the local metabolism of its substrates and their resulting drug response.Ph.D