Abstract
Drugs that bind to benzodiazepine recognition sites of γ-aminobutyric acid type A receptor complexes may function as agonists in some behavioral assays and as antagonists in other behavioral assays. The present studies compared the effects of the benzodiazepines midazolam, flumazenil, bretazenil, Ro 41-7812, and Ro 42-8773 and the β-carboline, β-carboline-3-carboxylate-t-butyl ester (β-CCt) under two different types of schedule-controlled responding in squirrel monkeys. One group of monkeys responded under a fixed-ratio schedule of stimulus-shock termination, and a second group of monkeys responded under a multiple fixed-ratio schedule of food presentation involving suppressed and nonsuppressed behavior. Under the schedule of stimulus-shock termination, midazolam produced dose-related decreases in response rate, and these effects were surmountably antagonized by flumazenil, bretazenil, Ro 41-7812, Ro 42-8773, and β-CCt. Schild plot analysis of these data revealed the following mean pA2values: flumazenil, 7.18; bretazenil, 7.62; Ro 41-7812, 7.06; Ro 42-8773, 6.95. Apparent pA2 values were not calculated for β-CCt because the CL of the slope of the Schild plot included positive values. Under the multiple schedule, midazolam, bretazenil, and Ro 42-8773 dose-dependently increased rates of suppressed responding, whereas flumazenil, Ro 41-7812, and β-CCt had no significant rate-altering effects. Flumazenil antagonized the antisuppressant effects of midazolam and bretazenil; however, individual variability in these effects prohibited the determination of apparent pA2 values. These results indicate that in vivo pA2 values may be determined for benzodiazepine-site ligands. These results further demonstrate that some benzodiazepine-site ligands, e.g., bretazenil and Ro 42-8773, may function as both agonists and as competitive antagonists in vivo.
Footnotes
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Send reprint requests to: Carol A. Paronis, Ph.D., Behavioral Pharmacology Program, ADARC/McLean Hospital, 115 Mill St., Belmont, MA. E-mail: cparonis{at}hms.harvard.edu
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↵1 This work was supported by National Institutes of Health Grants DA11453 and DA03774. Preliminary results of this work were presented at the annual meetings of the American Society for Pharmacology and Experimental Therapeutics, San Diego, CA, 1997 and the College on Problems of Drug Dependence, Nashville, TN, 1997.
- Abbreviations:
- β-CCt
- β-carboline-3-carboxylate-t-butyl ester
- FR
- fixed-ratio
- GABA
- γ-aminobutyric acid
- EKC
- ethylketocyclazocine
- Received February 19, 1999.
- Accepted May 10, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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