Evaluation of Taranabant (MK-0364) for its Self-Administration in Rhesus Monkeys and for its Discriminative Stimulus Effects in Rats

Taranabant (aka, MK-0364) was tested in rhesus monkeys that were trained to self-administer cocaine and in rats that were trained to discriminate Delta(9)-Tetrahydrocannabinol (THC) from vehicle in order to facilitate inferences about taranabant's potential to produce subjective effects similar to THC and to be used for recreational purposes (i.e., for its potential abuse liability). Four rhesus monkeys with chronically implanted intravenous catheters were trained to lever press according to fixed-ratio 50 (FR50) schedules reinforced with infusions of 0.03 or 0.01 mg/kg cocaine during daily, 1-h experimental sessions. During substitution tests, cocaine was replaced with a test close (0.001-0.1 mg/kg) of taranabant for four, consecutive daily sessions. Additionally, 10 adult male Long-Evans hooded rats were trained to discriminate 3 mg/kg i.p. THC from vehicle Using a food-reinforced, lever press procedure. Following training, doses of THC (0.1-10 mg/kg i.p.) and taranabant (0.3-17 mg/kg i.p.) were tested. None of the four monkeys self-administered taranabant above vehicle-control levels, and for three of the monkeys levels of responding were, at times, lower than those of vehicle itself. During discrimination tests, increases in the dose of THC or taranabant resulted in ED50 values (+/- 95% CI) of 9.65 mg/kg (7.03-13.27) and of 20.51 mg/kg (8.13-51.64), respectively, for reducing response rates. THC, but not taranabant, dose-dependently generalized to the 3-mg/kg THC discriminative Stimulus at levels of 80% and above. These results indicate that taranabant does not exhibit THC-like agonistic activity in vivo, and consequentially suggest it would be Unlikely that it would have a THC-like abuse potential. Drug Dev Res 70: 577-584, 2009. (C) 2009 Wiley-Liss, Inc.