title: Antagonism of the discriminative stimulus effects of positive gamma-aminobutyric acid(A) modulators in rhesus monkeys discriminating midazolam.
abstract: The extent to which individual subtypes of benzodiazepine receptors are functionally independent has not been elucidated in vivo. This study used apparent pA(2) analysis to test the hypothesis that a single receptor subtype mediates the discriminative stimulus effects of midazolam, triazolam, and diazepam, three positive gamma-aminobutyric acid(A) (GABA(A)) 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 GABA(A) modulator flumazenil shifted dose-effect curves for triazolam and diazepam to the right, and the negative GABA(A) modulators Ro 15-4513 and ethyl beta-carboline-3-carboxylate (beta-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 pA(2) 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 beta-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 pA(2) 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, beta-CCE and midazolam do not appear to interact in a simple, competitive manner.
authors.affiliation: Department of Pharmacology, Louisiana State University Health Sciences Center, New Orleans, USA.
authors.forename: S
authors.initials: S
authors.lastname: Lelas
authors.forename: L R
authors.initials: LR
authors.lastname: Gerak
authors.forename: C P
authors.initials: CP
authors.lastname: France
mesh_terms: D000818:Animals; D001386:Azides / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology; D002243:Carbolines / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D004193:Discrimination Learning / Q000187:drug effects*; D004336:Drug Antagonism; D005260:Female; D005442:Flumazenil / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology*; D008253:Macaca mulatta; D008297:Male; D008874:Midazolam / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects*
chemical_list: D001386:Azides; D002243:Carbolines; D018757:GABA Modulators; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005442:Flumazenil; C024915:beta-carboline-3-carboxylic acid ethyl ester; C042957:Ro 15-4513; D003975:Diazepam; D008874:Midazolam