Pharmacokinetic and pharmacodynamic analyses of cocaine and its metabolites in behaviorally divergent inbred mouse strains.
Pharmacokinetic and pharmacodynamic analyses of cocaine and its metabolites in behaviorally divergent inbred mouse strains.
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可卡因及其代谢物在行为不同的近交系小鼠体内的药代动力学和药效学分析。
DOI：
10.1111/gbb.12666
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Tarantino LM
中科院分区：
文献类型：
--
作者：
Zhu J;Beechinor RJ;Thompson T;Schorzman AN;Zamboni W;Crona DJ;Weiner DL;Tarantino LM
可卡因是一种精神兴奋剂，有很高的滥用和成瘾的可能性。可卡因使用障碍的风险部分由遗传因素驱动。成瘾相关行为的动物模型已被证明可用于研究遗传和非遗传对药物反应的贡献。在先前的研究中，我们研究了遗传多样的近交系小鼠品系对可卡因的初始运动敏感性。这项工作突出了药物动力学在可卡因初始自发反应中的相关性，但受到单次剂量和两个采样点的限制。本研究的目的是表征可卡因及其代谢产物（去甲可卡因和苯甲酰芽子碱）在对可卡因表现出极端运动反应的6个近交系小鼠品系（I/LnJ，C57 BL/6 J，FVB/NJ，BTBR T+ tf/J，LG/J，LP/J）中的药代动力学和药效学。以4种剂量之一对小鼠施用可卡因，并在5个不同的时间点分析血浆和脑组织中可卡因、去甲可卡因和苯甲酰芽子碱的浓度。对可卡因的初始运动敏感性用作药效学终点。我们开发了一个经验群体PK模型，同时表征可卡因，去甲可卡因，和benzoylecgonine在血浆和脑组织。我们观察到在脑区室中发生的菌株间变异性，这可能导致选定菌株之间的药效学差异。我们目前的工作为未来的研究铺平了道路，以探索菌株特异性药代动力学差异，并确定药代动力学以外的因素，这些因素是负责不同的行为反应可卡因在这些近交系小鼠品系。
Cocaine is a psychostimulant with a high potential for abuse and addiction. Risk for cocaine use disorder is driven, in part, by genetic factors. Animal models of addiction-relevant behaviors have proven useful for studying both genetic and non-genetic contributions to drug response. In a previous study, we examined initial locomotor sensitivity to cocaine in genetically diverse inbred mouse strains. That work highlighted the relevance of pharmacokinetics in initial locomotor response to cocaine but was limited by a single dose and two sampling points. The objective of the present study was to characterize the pharmacokinetics and pharmacodynamics of cocaine and its metabolites (norcocaine and benzoylecgonine) in 6 inbred mouse strains (I/LnJ, C57BL/6J, FVB/NJ, BTBR T+ tf/J, LG/J, LP/J) that exhibit extreme locomotor responses to cocaine. Mice were administered cocaine at one of 4 doses and concentrations of cocaine, norcocaine, and benzoylecgonine were analyzed in both plasma and brain tissue at 5 different time points. Initial locomotor sensitivity to cocaine was used as a pharmacodynamic endpoint. We developed an empirical population PK model that simultaneously characterizes cocaine, norcocaine, and benzoylecgonine in plasma and brain tissues. We observed interstrain variability occurring in the brain compartment that may contribute to pharmacodynamic differences amongst select strains. Our current work paves the way for future studies to explore strain-specific pharmacokinetic differences and identify factors other than pharmacokinetics that are responsible for the diverse behavioral response to cocaine across these inbred mouse strains.
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影响因子：
3.8
作者：
DEAN, RA;HARPER, ET;BOSRON, WF
通讯作者：
BOSRON, WF
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3.6
作者：
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通讯作者：
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2.2
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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