Drug discrimination analysis of partial agonists at the benzodiazepine site. I. Differential effects of U-78875 across training conditions in baboons and rats.
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.
Ator
N A
NA
Behavioral Biology Research Center, Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland, USA. ator@welchlink.welch.jhu.edu
Griffiths
R R
RR
D000161:Acoustic Stimulation; D000284:Administration, Oral; D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000494:pharmacology*; D003216:Conditioning, Operant; D003975:Diazepam / Q000008:administration & dosage / Q000494:pharmacology*; D004192:Discrimination, Psychological / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D058785:GABA-A Receptor Agonists; D007274:Injections, Intraperitoneal; D008140:Lorazepam / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D010069:Oxadiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D010215:Papio; D010424:Pentobarbital / Q000008:administration & dosage / Q000494:pharmacology*; D010775:Photic Stimulation; D011810:Quinoxalines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans
D014151:Anti-Anxiety Agents; D058785:GABA-A Receptor Agonists; D010069:Oxadiazoles; D011810:Quinoxalines; D010424:Pentobarbital; D008140:Lorazepam; D003975:Diazepam; C069443:panadiplon