Balcells-Olivero M, Cousins M S, Seiden L S
The University of Chicago, Department of Pharmacological and Physiological Sciences, Chicago, Illinois 60637, USA.
J Pharmacol Exp Ther. 1998 Aug;286(2):742-52.
Several compounds were tested on the differential-reinforcement-of-low-rate 72-sec (DRL 72-sec) schedule, a behavioral screen to determine putative antidepressants; these compounds were evaluated in two outbred stocks of rats, Harlan and Holtzman Sprague-Dawley rats. A dose-response determination for the tricyclic antidepressants, imipramine and desipramine, the selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, fluoxetine, the 5-HT2 receptor antagonist, ketanserin, the 5-HT1A receptor agonist, (+/-)8-hydroxy-di-propylamino tetralin (8-OH-DPAT) and the dopamine releasing compound, amphetamine, were assessed in both rat stocks. The two stocks of rats differed in their baseline performance on the DRL 72-sec schedule. The Harlan rats had a higher reinforcement rate and a lower response rate than the Holtzman rats. In Holtzman, but not in Harlan rats, imipramine, ketanserin, fluoxetine and 8-OH-DPAT increased reinforcement rate and decreased response rate on the DRL 72-sec schedule, confirming previous studies. However, desipramine was the only drug to increase reinforcement rate and decrease response rate in both Holtzman and Harlan rats; in Harlan rats, drugs that primarily act upon the 5-HT system, imipramine, ketanserin, fluoxetine and 8-OH-DPAT, disrupted the DRL 72-sec performance and did not increase the number of reinforcements over baseline as was seen in Holtzman rats. Amphetamine disrupted DRL 72-sec performance in both Holtzman and Harlan rats in a similar manner. The hypothermic response to 8-OH-DPAT was also assessed in the two stocks of rats; Holtzman rats had a smaller decrease in core body temperature than Harlan rats. The observed behavioral and pharmacological differences between Holtzman and Harlan rat stocks may be genetically and/or environmentally mediated.
在低速率72秒差异强化（DRL 72秒）程序下对几种化合物进行了测试，这是一种用于确定假定抗抑郁药的行为筛选方法；这些化合物在两种远交系大鼠（哈兰大鼠和霍尔茨曼斯普拉格-道利大鼠）中进行了评估。对三环类抗抑郁药丙咪嗪和地昔帕明、选择性5-羟色胺（5-HT）再摄取抑制剂氟西汀、5-HT2受体拮抗剂酮色林、5-HT1A受体激动剂（±）8-羟基二丙基氨基四氢萘（8-OH-DPAT）以及多巴胺释放化合物苯丙胺进行了剂量反应测定，两种大鼠品系均参与评估。两种大鼠品系在DRL 72秒程序的基线表现上存在差异。哈兰大鼠的强化率较高，反应率低于霍尔茨曼大鼠。在霍尔茨曼大鼠中，但在哈兰大鼠中未出现，丙咪嗪、酮色林、氟西汀和8-OH-DPAT在DRL 72秒程序下提高了强化率并降低了反应率，这证实了先前的研究。然而，地昔帕明是唯一一种在霍尔茨曼大鼠和哈兰大鼠中均提高强化率并降低反应率的药物；在哈兰大鼠中，主要作用于5-HT系统的药物丙咪嗪、酮色林、氟西汀和8-OH-DPAT破坏了DRL 72秒的表现，并且没有像在霍尔茨曼大鼠中那样比基线增加强化次数。苯丙胺以类似方式破坏了霍尔茨曼大鼠和哈兰大鼠的DRL 72秒表现。还评估了两种大鼠品系对8-OH-DPAT的体温降低反应；霍尔茨曼大鼠的核心体温下降幅度小于哈兰大鼠。观察到的霍尔茨曼大鼠和哈兰大鼠品系之间的行为和药理学差异可能是由基因和/或环境介导的。
