Comparison of the Psychopharmacological Effects of Tiletamine and Ketamine in Rodents

Piotr Popik, Małgorzata Hołuj, Tomasz Kos, Gabriel Nowak, Tadeusz Librowski, Kinga Sałat

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.