Using the self-administration of apomorphine and cocaine to measure the pharmacodynamic potencies and pharmacokinetics of competitive dopamine receptor antagonists.
Using the self-administration of apomorphine and cocaine to measure the pharmacodynamic potencies and pharmacokinetics of competitive dopamine receptor antagonists.
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DOI：
10.1016/j.jneumeth.2010.10.017
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发表时间：
2011-01-15
影响因子：
3
通讯作者：
Tsibulsky, Vladimir L.
中科院分区：
文献类型：
--
作者：
Norman, Andrew B.;Tabet, Michael R.;Norman, Mantana K.;Tsibulsky, Vladimir L.
关键词：
竞争性多巴胺受体拮抗剂可加速精神运动兴奋剂的自我给药。根据竞争性拮抗的药理学理论，拮抗剂可提高等量激动剂的浓度。在自我管理范式中，这被假定为饱腹感阈值或Cmin。作为拮抗剂剂量函数的饱足阈值(激动剂浓度比)的比例增加的幅度应反映拮抗剂的药效学效力。这种效应的时间进程应该反映受体拮抗剂占有率的变化速度，从而反映拮抗剂浓度，即药代动力学。大鼠以稳定的速率给予阿朴吗啡或可卡因，然后静脉注射。与四个竞争性的D1样或D2样多巴胺受体拮抗剂中的一个，会议继续进行。计算每次给药时的激动剂浓度(饱腹感阈值)。拮抗剂加速了两种激动剂的自我给药，并伴随着计算的饱腹感阈值的增加。最大激动剂浓度比与拮抗剂剂量成正比。激动剂浓度比变化的时程与激动剂和拮抗剂的剂量无关。最大激动剂浓度比作为拮抗剂剂量函数的SChild分析允许测量表观PA2(或K剂量)。拮抗剂K剂量值应为行为药理学中受体的鉴定提供定量依据。该测定系统还可以测量拮抗剂从脑中消除的药代动力学。激动剂自身给药是一种灵敏的体内药理测定系统，可为拮抗剂作用的药代动力学/药效学模型提供有用的信息。
Competitive dopamine receptor antagonists accelerate psychomotor stimulant self-administration. According to pharmacological theory of competitive antagonism antagonists raise the equiactive agonist concentration. In the self-administration paradigm this is assumed to be the satiety threshold or Cmin. The magnitude of the proportional increase in satiety threshold (agonist concentration ratio) as a function of antagonist dose should reflect the antagonist pharmacodynamic potency. The time course of this effect should reflect the rate of change of antagonist occupancy of receptors and, therefore, antagonist concentration i.e. pharmacokinetics. Rats self-administered apomorphine or cocaine at a stable rate and were then injected i.v. with one of four competitive D1–like or D2–like dopamine receptor antagonists and the session continued. The agonist concentrations at the time of each self-administration (satiety thresholds) were calculated during the session. The antagonists accelerated self-administration of both agonists with a concomitant increase in the calculated satiety thresholds. The maximum agonist concentration ratio was proportional to the dose of antagonist. The time courses of the changes in agonist concentration ratio were independent of the agonist and of the dose of antagonist. Schild analysis of the maximum agonist concentration ratio as a function of the antagonist dose allowed apparent pA2 (or Kdose) to be measured. Antagonist Kdose values should provide a quantitative basis for receptor identification in behavioral pharmacology. The assay system may also measure the pharmacokinetics of antagonist elimination from the brain. Agonist self-administration represents a sensitive in vivo pharmacological assay system that provides information useful for pharmacokinetic/pharmacodynamic modeling of antagonist effects.
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影响因子：
3.4
作者：
Ahmed, SH;Koob, GF
通讯作者：
Koob, GF
DOI：
10.1111/j.1476-5381.1947.tb00336.x
发表时间：
1947-01-01
期刊：
BRITISH JOURNAL OF PHARMACOLOGY AND CHEMOTHERAPY
影响因子：
--
作者：
SCHILD, HO
通讯作者：
SCHILD, HO
影响因子：
3.6
作者：
BAXTER, BL;GLUCKMAN, MI;SCERNI, RA
通讯作者：
SCERNI, RA
影响因子：
3.4
作者：
HIETALA, J;SEPPALA, T;SYVALAHTI, E
通讯作者：
SYVALAHTI, E
影响因子：
5
作者：
RICHELSON, E;NELSON, A
通讯作者：
NELSON, A