Garcia Kristine L P, Coen Kathy, Miksys Sharon, Lê Anh Dzung, Tyndale Rachel F
1] Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada [2] Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada [3] Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Neuropsychopharmacology. 2015 Jul;40(8):1910-8. doi: 10.1038/npp.2015.40. Epub 2015 Feb 5.
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.
细胞色素P450 2B（CYP2B）酶在人和大鼠的大脑中均有表达，可代谢多种作用于中枢神经系统（CNS）的药物。编码人类CYP2B6的基因具有高度多态性，大脑中该酶水平的变化可能导致脑内药物水平改变。CYP2B可代谢香烟中的主要精神活性成分尼古丁；如果大脑中CYP2B活性的改变会影响尼古丁在脑内的水平，那么就可能影响尼古丁介导的行为。为了对此进行研究，将一种对CYP2B具有选择性的基于机制的抑制剂C8-黄原酸盐（20μg）经脑室内（ICV）注射到大鼠脑内，22小时后，在静脉注射尼古丁（150μg/kg）后，通过体内微透析法测量尼古丁水平。与溶剂预处理相比，C8-黄原酸盐预处理后15至30分钟的脑内尼古丁水平以及0至45分钟的药时曲线下面积（AUC0-45 min）均高出两倍（p<0.05）；外周尼古丁水平无差异。然后给大鼠进行C8-黄原酸盐/人工脑脊液（ASCF）的ICV预处理，并以每输注剂量3.75-30μg/kg进行静脉尼古丁自我给药。C8-黄原酸盐预处理增加了渐进比率中的反应（每输注剂量15μg/kg，p<0.05）。在另一组实验中，C8-黄原酸盐将获得自我给药的大鼠百分比（每输注剂量7.5μg/kg，p<0.05）从溶剂预处理后的40%提高到100%，行为结束时测量的外周尼古丁水平无差异。在第三组实验中，C8-黄原酸盐增加了达到消退标准所需的实验次数（p<0.05）。这些数据共同表明，大脑中的CYP2B活性可独立于肝脏代谢影响尼古丁在脑内的水平及随后的行为。这表明CYP2B脑内水平不同的人类吸烟者可能有不同的尼古丁水平和强化作用，这可能在吸烟行为和成瘾中起作用。
