Faculty of Health Sciences, Jagiellonian University Medical College, 12 Michałowskiego Street, 31-126, Kraków, Poland.
Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343, Kraków, Poland.
Neurotox Res. 2017 Nov;32(4):544-554. doi: 10.1007/s12640-017-9759-0. Epub 2017 Jun 2.
The glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine (KET) produces rapid and sustained antidepressant effects in patients. Tiletamine (TIL; 2-ethylamino-2-thiophen-2-yl-cyclohexan-1-one) is another uncompetitive NMDA receptor antagonist, used in a medical (veterinary) setting as an anesthetic tranquilizer. Here, we compared the behavioral actions of KET and TIL in a variety of tests, focusing on antidepressant-like and dissociative-like effects in mice and rats. The minimum effective doses of KET and TIL were 10 mg/kg to reduce mouse forced swim test immobility and 15 mg/kg to reduce marble-burying behavior. However, at similar doses, both compounds diminished locomotor activity and disturbed learning processes in the mouse passive avoidance test and the rat novel object recognition test. KET and TIL also reduced social behavior and accompanying 50-kHz "happy" ultrasonic vocalizations (USVs) in rats. TIL (5-15 mg/kg) displayed additional anxiolytic-like effects in the four-plate test. Neither KET nor TIL affected pain response in the hot plate test. Examination of the "side effects" revealed that only at the highest doses investigated did both compounds produce motor deficits in the rotarod test in mice. While KET produced behavioral effects at doses comparable between species, in the rats, TIL was ~10 times more potent than in the mice. In summary, antidepressant-like properties of both KET and TIL are similar, as are their adverse effect liabilities. We suggest that TIL could be an alternative to KET as an antidepressant with an additional anxiolytic-like profile.
谷氨酸 N-甲基-D-天冬氨酸（NMDA）受体拮抗剂氯胺酮（KET）可迅速且持续地改善患者的抑郁症状。替来他明（TIL；2-乙氨基-2-噻吩-2-基环己烷-1-酮）是另一种非竞争性 NMDA 受体拮抗剂，在医疗（兽医）环境中用作麻醉镇静剂。在这里，我们比较了 KET 和 TIL 在各种测试中的行为作用，重点研究了它们在小鼠和大鼠中的抗抑郁样和分离样作用。KET 和 TIL 的最小有效剂量分别为 10mg/kg 以减少小鼠强迫游泳试验中的不动性和 15mg/kg 以减少大理石掩埋行为。然而，在类似剂量下，两种化合物都会减少小鼠被动回避试验和大鼠新物体识别试验中的运动活性和干扰学习过程。KET 和 TIL 还减少了大鼠的社交行为和伴随的 50-kHz“快乐”超声发声（USVs）。TIL（5-15mg/kg）在四板试验中表现出额外的抗焦虑样作用。KET 和 TIL 均不影响热板试验中的疼痛反应。对“副作用”的检查表明，只有在研究的最高剂量下，两种化合物才会导致小鼠在旋转棒试验中出现运动缺陷。虽然 KET 在种间可比剂量下产生行为作用，但在大鼠中，TIL 的效力比小鼠高约 10 倍。总之，KET 和 TIL 的抗抑郁样特性相似，其不良反应也相似。我们认为 TIL 可以替代 KET 作为一种具有额外抗焦虑样作用的抗抑郁药。
