Selectivity in generalization to GABAergic drugs in midazolam-trained baboons

When barbiturates have been tested in animals trained to discriminate the intravenous benzodiazepine (Bz) anesthetic midazolam, squirrel monkeys and pigeons did not reliably generalize to barbiturates but rats did. To explore this unexpected phenomenon in another species and to extend the midazolam generalization profile to GABAergic compounds not previously tested, five baboons were trained to discriminate midazolam maleate (0.32 mg/kg iv) from saline under a two-lever procedure. In tests 10 min after dose delivery, the partial agonist imidazenil, the full agonist chlordiazepoxide, and the receptor-subtype-selective hypnotic zolpidem fully shared discriminative effects with midazolam. The barbiturate pentobarbital did so in only one of five baboons, and the intravenous anesthetic propofol failed to do so in the three baboons tested. Testing 1 min after dose delivery shifted midazolam and zolpidem curves to the left and increased generalization to propofol but not pentobarbital. Taken together with previous published data, partial or full agonism at the Bz binding site appears sufficient for midazolam-like discriminative effects in nonhuman primates, pigeons, and rodents, and modulation through the anesthetic site is sufficient in baboons. However, to date, positive modulation of GABA through the barbiturate site is not generally sufficient for this effect in nonhuman primates and pigeons although it is in rodents.