Department of Psychiatry and Behavioral Neuroscience, College of Medicine, University of Cincinnati, 2170 E. Galbraith Rd., Cincinnati, OH 45237-0506, USA.
J Pharmacol Exp Ther. 2011 Aug;338(2):724-8. doi: 10.1124/jpet.111.183244. Epub 2011 May 23.
Differences in the time to maximal effect (T(max)) of a series of dopamine receptor antagonists on the self-administration of cocaine are not consistent with their lipophilicity (octanol-water partition coefficients at pH 7.4) and expected rapid entry into the brain after intravenous injection. It was hypothesized that the T(max) reflects the time required for maximal occupancy of receptors, which would occur as equilibrium was approached. If so, the T(max) should be related to the affinity for the relevant receptor population. This hypothesis was tested using a series of nine antagonists having a 2500-fold range of K(i) or K(d) values for D(2)-like dopamine receptors. Rats self-administered cocaine at regular intervals and then were injected intravenously with a dose of antagonist, and the self-administration of cocaine was continued for 6 to 10 h. The level of cocaine at the time of every self-administration (satiety threshold) was calculated throughout the session. The satiety threshold was stable before the injection of antagonist and then increased approximately 3-fold over the baseline value at doses of antagonists selected to produce this approximately equivalent maximal magnitude of effect (maximum increase in the equiactive cocaine concentration, satiety threshold; C(max)). Despite the similar C(max), the mean T(max) varied between 5 and 157 min across this series of antagonists. Furthermore, there was a strong and significant correlation between the in vivo T(max) values for each antagonist and the affinity for D(2)-like dopamine receptors measured in vitro. It is concluded that the cocaine self-administration paradigm offers a reliable and predictive bioassay for measuring the affinity of a competitive antagonist for D(2)-like dopamine receptors.
一系列多巴胺受体拮抗剂对可卡因自身给药的最大效应时间（T(max)）的差异与它们的亲脂性（pH7.4 时的辛醇-水分配系数）和预期的静脉注射后快速进入大脑不一致。假设 T(max)反映了达到受体最大占有率所需的时间，这将在接近平衡时发生。如果是这样，T(max)应该与相关受体群体的亲和力有关。使用一系列具有 2500 倍 K(i)或 K(d)值范围的 9 种拮抗剂来检验这一假设，用于 D2 样多巴胺受体。大鼠定期自行给予可卡因，然后静脉注射一剂拮抗剂，并继续进行 6 至 10 小时的可卡因自身给药。在整个实验过程中，计算每次自我给药时的可卡因水平（饱腹感阈值）。在注射拮抗剂之前，饱腹感阈值是稳定的，然后在选择产生这种等效最大效应幅度（等效可卡因浓度的最大增加，饱腹感阈值；C(max)）的拮抗剂剂量下，饱腹感阈值增加约 3 倍。尽管 C(max)相似，但在这一系列拮抗剂中，平均 T(max)在 5 至 157 分钟之间变化。此外，每种拮抗剂的体内 T(max)值与在体外测量的 D2 样多巴胺受体亲和力之间存在强烈且显著的相关性。结论是，可卡因自身给药范式为测量竞争性拮抗剂对 D2 样多巴胺受体的亲和力提供了一种可靠和可预测的生物测定法。
