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.

Brain CYP2B induction can decrease nicotine levels in the brain

“…We have recently shown that selective inhibition of CYP2B in the brain by intracerebral injection of a CYP2B inhibitor can increase nicotine levels in the brain, but not in the plasma, following a single intravenous nicotine injection (Garcia et al , 2015). Thus, reducing brain CYP2B activity can influence nicotine levels within the brain without influencing systemic levels or hepatic metabolism.…”

“…The effect of CYP2B induction on both of these potential changes in brain drug levels can be investigated using brain microdialysis, where brain drug levels can be repeatedly measured. We have previously shown that acutely inhibiting brain CYP2B activity can increase local brain nicotine levels (Garcia et al , 2015), thus this study aimed to investigate the effect of altering CYP2B activity on brain nicotine levels through enzyme induction using microdialysis to measure brain nicotine levels over time (Garcia et al , 2015). We expect that CYP2B induction in the brain, by increasing CYP2B activity, would decrease brain nicotine levels.…”

Variation in CYP2A6 and tobacco dependence throughout adolescence and in young adult smokers

“…Together with our findings, these data suggest that the CYP2B6*6 allele is associated with a higher risk of nicotine dependence in adulthood; over adolescence we speculate that the risk conferred by CYP2B6 slow metabolism increases. Data from an animal model suggests variable brain CYP2B activity may influence nicotine metabolism within the brain, in turn affecting nicotine-mediated behaviours (Garcia et al, 2015). In rats, the inhibition of brain CYP2B activity through intracerebroventricular injection of a selective CYP2B inhibitor led to higher rates of acquisition of nicotine self-administration behavior but no difference in level of responding among dependent animals; this was performed without altering peripheral nicotine levels or metabolism (Garcia et al, 2015).…”

“…Data from an animal model suggests variable brain CYP2B activity may influence nicotine metabolism within the brain, in turn affecting nicotine-mediated behaviours (Garcia et al, 2015). In rats, the inhibition of brain CYP2B activity through intracerebroventricular injection of a selective CYP2B inhibitor led to higher rates of acquisition of nicotine self-administration behavior but no difference in level of responding among dependent animals; this was performed without altering peripheral nicotine levels or metabolism (Garcia et al, 2015). It is possible that CYP2B6 variation within human brain may lead to altered central metabolism of nicotine, which may account for the observed differences in nicotine dependence (Riccardi et al, 2015) and cessation outcomes (Lee et al, 2007a), while having no effect on the level of consumption as observed here.…”

“Target-Site” Drug Metabolism and Transport

“…Together this suggests that variable CYP2B activity within the brain can alter the rate of inactivation of propofol and influence drug response. Recently, it has also been shown that inhibiting CYP2B in rat brain can also alter nicotine levels in the brain, measured by microdialysis, and resulting nicotine self-administration (Garcia et al, 2015).…”