Abstract
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.
Footnotes
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Send reprint requests to: Nancy A. Ator, Ph.D., Behavioral Biology Research Center, 5510 Nathan Shock Dr., Ste. 3000, Johns Hopkins Bayview Campus, Baltimore, MD 21224-6823. E-mail:ator{at}welchlink.welch.jhu.edu
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↵1 This work was supported by Grant DA04133 awarded by the National Institute on Drug Abuse. Portions of these findings were reported initially at the meetings of the European Behavioral Pharmacology Society (Cambridge, England), 1992; Society for the Stimulus Properties of Drugs (Washington, DC) in 1992; Society for Neuroscience (Ator et al., 1995); and Behavioral Pharmacology Society (Philadelphia, PA), 1997.
- Abbreviations:
- Bz
- benzodiazepine
- GABA
- γ-aminobutyric acid
- ND
- no drug
- U-78875
- 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5-(1-methylethyl)imidazol(1,5-a)quinoxalin-4(5H)-o-ne
- Received August 4, 1998.
- Accepted February 2, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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