Department of Toxicology, Collegium Medicum, Jagiellonian University, Medyczna 9, PL 30-688 Kraków, Poland.
Pharmacol Rep. 2012;64(6):1337-49. doi: 10.1016/s1734-1140(12)70931-3.
We employed a cocaine intravenous self-administration model based on positive reinforcement of animals' instrumental reactions (i.e., lever pressing) rewarded by a dose of the drug. We also carried out simultaneous characterization of the pharmacokinetics of cocaine and its metabolites in rats during withdrawal; in this part of the experiments, we investigated the cocaine (2 mg/kg, iv)-induced changes in the distribution, rate constant, clearance and t₁/₂ of the parent drug and its metabolites in different structures of the brain and in peripheral tissues.
By using liquid chromatography-tandem mass spectrometry (LC/MS/MS) we measured the levels of cocaine and its major metabolites.
Our results demonstrate differences in the levels of cocaine after cocaine self-administration in the rat, with the highest concentration seen in the striatum and the lowest in the cerebellum. Cocaine metabolites determined in the rat brain remained at very low levels (benzoylecgonine), irrespectively of the brain area, whereas the norcocaine concentration varied from 1.56 μg/g (the nucleus accumbens) to 2.73 μg/g (the striatum).
A tandem LC/MS/MS is a valid method for evaluation of brain and peripheral levels of cocaine and its metabolites. Our results demonstrate brain area-dependent differences in the levels of cocaine after its self-administration in the rat. There were also differences in pharmacokinetic parameters among the brain areas and peripheral tissues following a bolus iv injection of cocaine to rats withdrawn from cocaine; among brain structures the slowest metabolic rate was detected for the striatum.
我们采用了一种基于动物工具反应（即按压杠杆）的正强化的可卡因静脉自我给药模型，该反应由药物剂量奖励。我们还同时对可卡因戒断期间大鼠体内可卡因及其代谢物的药代动力学进行了特征描述；在这部分实验中，我们研究了可卡因（2mg/kg，iv）对脑内不同结构和外周组织中母体药物及其代谢物分布、速率常数、清除率和 t₁/₂的影响。
我们使用液相色谱-串联质谱（LC/MS/MS）来测量可卡因及其主要代谢物的水平。
我们的结果表明，在大鼠可卡因自我给药后，可卡因的水平存在差异，纹状体中的浓度最高，小脑中的浓度最低。在大鼠脑内测定的可卡因代谢物浓度仍然非常低（苯甲酰古柯碱），与脑区无关，而去甲可卡因浓度从 1.56μg/g（伏隔核）到 2.73μg/g（纹状体）不等。
串联 LC/MS/MS 是评估大脑和外周可卡因及其代谢物水平的有效方法。我们的结果表明，在大鼠可卡因自我给药后，脑区依赖的可卡因水平存在差异。在可卡因戒断大鼠静脉注射可卡因后，大脑区域和外周组织之间的药代动力学参数也存在差异；在脑结构中，纹状体的代谢率最慢。
