Accumulation of nicotine and its metabolites in rat brain after intermittent or continuous peripheral administration of [2'-(14)C]nicotine.
Accumulation of nicotine and its metabolites in rat brain after intermittent or continuous peripheral administration of [2'-(14)C]nicotine.
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发表时间：
2001-05
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通讯作者：
Omar A. Ghosheh;L. Dwoskin;Dennis K. Miller;P. Crooks
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作者：
Omar A. Ghosheh;L. Dwoskin;Dennis K. Miller;P. Crooks
测定大鼠间断和连续给予[2 '-（14）C]尼古丁后脑和血液中尼古丁、可替宁和去甲尼古丁的浓度，以评估重复给予尼古丁后尼古丁代谢物在脑中的蓄积。对于间歇性研究，对大鼠进行s.c. 1至10剂尼古丁（0.3 mg/kg，15或25微Ci [2 '-（14）C]尼古丁;注射间隔30分钟）。对于连续给药研究，将大鼠皮下植入。使用渗透微型泵输送尼古丁（0.8 mg/kg/天，25或50 microCi [2 '-（14）C]尼古丁，持续1-21天）。收集全脑和躯干血液。通过高压液相放射色谱法测定[2 '-（14）C]尼古丁及其代谢产物的浓度。10次注射后，尼古丁、可替宁和去甲尼古丁的脑浓度分别增加2倍、12倍和9倍，在第5次注射后达到平台期。脑血比表明，随着注射次数的增加，去甲尼古丁向大脑的优先分布增强。在连续输注的21天期间，血液尼古丁和去甲尼古丁浓度保持相对恒定，而脑中的浓度增加约4倍。一般而言，脑和血液中的可替宁浓度在输注期间未发生变化。脑/血液比表明，在尼古丁输注的天数内，尼古丁分布到大脑中的增加。结果表明，重复给予尼古丁后，尼古丁及其代谢产物均在脑中蓄积，并表明脑尼古丁浓度不能从血浆可替宁或尼古丁浓度外推。因此，尼古丁重复给药后的去甲尼古丁蓄积表明，该代谢产物在尼古丁的神经药理学作用中起着促进作用。
Concentrations of nicotine, cotinine, and nornicotine in brain and blood following both intermittent and continuous administration of [2'-(14)C]nicotine to rats were determined to assess nicotine metabolite accumulation in brain following repeated nicotine administration. For intermittent studies, rats were administered s.c. 1 to 10 doses of nicotine (0.3 mg/kg, 15 or 25 microCi of [2'-(14)C]nicotine; 30-min interinjection interval). For continuous administration studies, rats were implanted s.c. with an osmotic minipump delivering nicotine (0.8 mg/kg/day, 25 or 50 microCi of [2'-(14)C]nicotine for 1-21 days). Whole brain and trunk blood was collected. The concentration of [2'-(14)C]nicotine and its metabolites was determined via high-pressure liquid radiochromatography. Brain concentrations of nicotine, cotinine, and nornicotine increased 2-, 12-, and 9-fold, respectively, following 10 injections, reaching a plateau following the fifth injection. Brain blood ratios indicate an enhanced preferential distribution of nornicotine to brain with increasing numbers of injections. Across the 21-day period of continuous infusion, blood nicotine and nornicotine concentrations remained relatively constant, whereas concentrations in brain increased approximately 4-fold. Generally, cotinine concentrations in brain and blood did not change across the infusion period. Brain/blood ratios indicate an increase in nicotine distribution into brain across days of nicotine infusion. Results demonstrate that both nicotine and its metabolites accumulate in brain following repeated nicotine administration, and indicate that brain nicotine concentration can not be extrapolated from plasma cotinine or nicotine concentrations. Thus, nornicotine accumulation following repeated nicotine administration suggests that this metabolite plays a contributory role in the neuropharmacological effects of nicotine.