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Vol. 294, Issue 3, 902-908, September 2000
-Aminobutyric AcidA Modulators in Rhesus Monkeys
Discriminating Midazolam1
Department of Pharmacology (S.L., L.G.R., C.P.F.) and Neuroscience
Center of Excellence (C.P.F.), Louisiana State University
Health Sciences Center, New Orleans, Louisiana
The extent to which individual subtypes of benzodiazepine receptors are
functionally independent has not been elucidated in vivo. This study
used apparent pA2 analysis to test the hypothesis that a
single receptor subtype mediates the discriminative stimulus effects of
midazolam, triazolam, and diazepam, three positive 
-aminobutyric
acidA (GABAA) modulators. Four rhesus monkeys
discriminated 0.56 mg/kg midazolam from vehicle under a fixed-ratio 5 schedule of stimulus-shock termination. Midazolam, triazolam, and
diazepam increased responding on the midazolam-appropriate lever. The
neutral GABAA modulator flumazenil shifted dose-effect
curves for triazolam and diazepam to the right, and the negative
GABAA modulators Ro 15-4513 and ethyl
-carboline-3-carboxylate (-CCE) shifted dose-effect curves for
midazolam and triazolam to the right. Slopes of Schild plots for
flumazenil and Ro 15-4513 conformed to unity. The apparent pA2 values were 7.41 and 7.69 for flumazenil in combination
with triazolam and diazepam, respectively, and 7.53 and 6.88 for Ro 15-4513 in combination with midazolam and triazolam, respectively. The
slope of the Schild plot for -CCE in combination with midazolam deviated from unity. Slopes of Schild plots obtained with flumazenil and Ro 15-4513 support the notion that a single benzodiazepine receptor
subtype mediates the effects of midazolam, triazolam, or diazepam. The
similarity in apparent pA2 values for flumazenil in
combination with triazolam and diazepam or for Ro 15-4513 in combination with midazolam and triazolam suggests that the same subtype
mediates the effects of these positive modulators. In contrast, -CCE
and midazolam do not appear to interact in a simple, competitive manner.
This article has been cited by other articles:
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  L. R. McMahon Characterization of Cannabinoid Agonists and Apparent pA2 Analysis of Cannabinoid Antagonists in Rhesus Monkeys Discriminating {Delta}9-Tetrahydrocannabinol J. Pharmacol. Exp. Ther., December 1, 2006; 319(3): 1211 - 1218. [Abstract] [Full Text] [PDF]
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L. R. McMahon and C. P. France Discriminative Stimulus Effects of Positive GABAA Modulators and Other Anxiolytics, Sedatives, and Anticonvulsants in Untreated and Diazepam-Treated Monkeys J. Pharmacol. Exp. Ther., January 1, 2003; 304(1): 109 - 120. [Abstract] [Full Text] [PDF]
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L. R. McMahon and C. P. France Daily Treatment with Diazepam Differentially Modifies Sensitivity to the Effects of gamma -Aminobutyric AcidA Modulators on Schedule-Controlled Responding in Rhesus Monkeys J. Pharmacol. Exp. Ther., March 1, 2002; 300(3): 1017 - 1025. [Abstract] [Full Text] [PDF]
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L. R. McMahon, L. R. Gerak, L. Carter, C. Ma, J. M. Cook, and C. P. France Discriminative Stimulus Effects of Benzodiazepine (BZ)1 Receptor-Selective Ligands in Rhesus Monkeys J. Pharmacol. Exp. Ther., February 1, 2002; 300(2): 505 - 512. [Abstract] [Full Text] [PDF]
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L. R. McMahon, L. R. Gerak, and C. P. France Potency of Positive gamma -Aminobutyric AcidA Modulators to Substitute for a Midazolam Discriminative Stimulus in Untreated Monkeys Does Not Predict Potency to Attenuate a Flumazenil Discriminative Stimulus in Diazepam-Treated Monkeys J. Pharmacol. Exp. Ther., September 1, 2001; 298(3): 1227 - 1235. [Abstract] [Full Text] [PDF]
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