Vol. 289, Issue 3, 1434-1446, June 1999

Drug Discrimination Analysis of Partial Agonists at the Benzodiazepine Site. I. Differential Effects of U-78875 Across Training Conditions in Baboons and Rats¹

Nancy A. Ator and Roland R. Griffiths

Behavioral Biology Research Center, Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland

The benzodiazepine receptor ligand U-78875 [3-(5-cyclopro pyl-1,2,4-oxadiazol-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 diazepam, 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 mg/kg i.p. in rats and 0.32 to 56 mg/kg orally in baboons. U-78875 occasioned drug-appropriate responding in pentobarbital-trained (ED₅₀ = 1.8 mg/kg) and 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 baboons or rats. In baboons that generalized to U-78875, discriminative effects were antagonized by flumazenil. The interaction of U-78875 with pentobarbital, diazepam, and lorazepam revealed further differences in its behavioral effects. U-78875 potentiated the effects of pentobarbital, even in baboons that did not generalize to U-78875, but U-78875 had little effect in combination with diazepam. In lorazepam-trained animals that did not generalize to it, U-78875 antagonized lorazepam's effects, but U-78875 neither antagonized nor potentiated lorazepam in animals that did generalize to U-78875. Thus, although U-78875 generally functioned as a benzodiazepine agonist in pentobarbital- and diazepam-trained animals, its unique effects in lorazepam-trained animals appear to reflect its in vitro profile as a partial agonist.