Antagonism of the discriminative stimulus effects of positive γ-aminobutyric acid(A) modulators in rhesus monkeys discriminating midazolam

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 γ-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 β-carboline-3-carboxylate (β-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 β-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, β-CCE and midazolam do not appear to interact in a simple, competitive manner.