Norman Andrew B, Buesing William R, Norman Mantana K, Tabet Michael R, Tsibulsky Vladimir L
Department of Psychiatry, Division of Neuroscience, College of Medicine, University of Cincinnati, Cincinnati, OH 45267-0559, USA.
Eur J Pharmacol. 2004 Jan 12;483(2-3):281-7. doi: 10.1016/j.ejphar.2003.10.040.
Rats that self-administered cocaine at unit doses between 0.75 and 12 micromol/kg with mean inter-injection intervals between approximately 2 and 18 min also reliably self-administered the cocaine analogue WIN 35,428 (beta-CFT; (-)-3 beta-(4-fluorophenyl)tropane-2 beta-carboxylic acid methyl ester) at unit doses between 0.1 and 1.6 micromol/kg with mean intervals between 10 and 116 min. The long inter-injection intervals of WIN 35,428 necessitated sessions of more than 12 h. The inter-injection intervals were regular and proportional to the unit dose, consistent with the satiety threshold model. Analysis of the mean intervals as a function of unit doses generated values for the mean satiety threshold of cocaine and WIN 35,428 of 6.10 and 0.87 micromol/kg, respectively. The mean t(1/2) for cocaine and WIN 35,428 were 11.1 and 69.4 min, respectively. The approximately 43-fold lower rate of consumption of WIN 35,428 relative to cocaine was a product of the seven-fold greater pharmacodynamic potency and the six-fold greater pharmacokinetic potency.
以0.75至12微摩尔/千克的单位剂量自行注射可卡因且平均注射间隔约为2至18分钟的大鼠，也能可靠地自行注射可卡因类似物WIN 35,428（β-CFT；（-）-3β-（4-氟苯基）托烷-2β-羧酸甲酯），其单位剂量为0.1至1.6微摩尔/千克，平均间隔为10至116分钟。WIN 35,428较长的注射间隔需要超过12小时的实验时段。注射间隔是规律的，并且与单位剂量成正比，这与饱腹感阈值模型一致。将平均间隔作为单位剂量的函数进行分析，得出可卡因和WIN 35,428的平均饱腹感阈值分别为6.10和0.87微摩尔/千克。可卡因和WIN 35,428的平均t(1/2)分别为11.1分钟和69.4分钟。WIN 35,428相对于可卡因约低43倍的消耗率是其药效学效力高7倍和药代动力学效力高6倍的结果。
