Drug discrimination analysis of partial agonists at the benzodiazepine site. I. Differential effects of U-78875 across training conditions in baboonsand rats

The benzodiazepine receptor ligand U-78875 [3-(5-cyclopro pyl-1,2,4-oxadiaz ol-3-yl)-5-(1-methylethyl)imidazol(1,5-a)quinoxalin-4(5H)-o-ne] was studied in rats trained to discriminate i.p. 1.0 mg/kg lorazepam, 1.0 mg/kg diazep am, or 10 mg/kg pentobarbital, and baboons trained to discriminate oral 1.8 mg/kg lorazepam or 10 mg/kg pentobarbital. U-78875 doses were 0.01 to 10 m g/kg i.p. in rats and 0.32 to 56 mg/kg orally in baboons. U-78875 occasione d drug-appropriate responding in pentobarbital-trained (ED50 = 1.8 mg/kg) a nd diazepam-trained (ED50 = 0.056 mg/kg) rats, but it occurred in only one pentobarbital-trained baboon and not in the majority of lorazepam-trained b aboons or rats. In baboons that generalized to U-78875, discriminative effe cts were antagonized by flumazenil. The interaction of U-78875 with pentoba rbital, diazepam, and lorazepam revealed further differences in its behavio ral effects, U-78875 potentiated the effects of pentobarbital, even in babo ons that did not generalize to U-78875, but U-78875 had little effect in co mbination with diazepam. In lorazepam trained animals that did not generali ze to it, U-78875 antagonized lorazepam's effects, but U-78875 neither anta gonized nor potentiated lorazepam in animals that did generalize to U-78875 . Thus, although U-78875 generally functioned as a benzodiazepine agonist i n pentobarbital- and diazepam-trained animals, its unique effects in loraze pam-trained animals appear to reflect its in vitro profile as a partial ago nist.