Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA.
J Neurosci Methods. 2011 Jan 15;194(2):252-8. doi: 10.1016/j.jneumeth.2010.10.017. Epub 2010 Oct 23.
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 C(min). 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 K(dose)) to be measured. Antagonist K(dose) 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.
竞争性多巴胺受体拮抗剂可加速精神兴奋剂的自我给药。根据竞争性拮抗的药理学理论，拮抗剂会提高等效激动剂的浓度。在自我给药范式中，这被认为是饱腹感阈值或 C(min)。作为拮抗剂剂量函数的饱腹感阈值（激动剂浓度比）的比例增加幅度应反映拮抗剂的药效强度。这种效应的时间过程应反映拮抗剂对受体占据的变化率，因此反映拮抗剂浓度，即药代动力学。大鼠以稳定的速度自行给予阿扑吗啡或可卡因，然后静脉注射四种竞争性 D₁样或 D₂样多巴胺受体拮抗剂之一，并继续进行。在会话期间计算每次自我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，同时增加了计算出的饱腹感阈值。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间过程与激动剂和拮抗剂的剂量无关。Schild 分析最大激动剂浓度比作为拮抗剂剂量的函数，允许测量表观 pA₂（或 K(dose)）。拮抗剂 K(dose) 值应为行为药理学中受体鉴定提供定量基础。该测定系统还可以测量拮抗剂从大脑中消除的药代动力学。激动剂自我给药代表一种敏感的体内药理学测定系统，可提供有用的信息，用于拮抗剂作用的药代动力学/药效动力学建模。
