PT - JOURNAL ARTICLE AU - Snjezana Lelas AU - Lisa R. Gerak AU - Charles P. France TI - Antagonism of the Discriminative Stimulus Effects of Positive γ-Aminobutyric Acid<sub>A</sub> Modulators in Rhesus Monkeys Discriminating Midazolam DP - 2000 Sep 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 902--908 VI - 294 IP - 3 4099 - http://jpet.aspetjournals.org/content/294/3/902.short 4100 - http://jpet.aspetjournals.org/content/294/3/902.full SO - J Pharmacol Exp Ther2000 Sep 01; 294 AB - 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 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 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. The American Society for Pharmacology and Experimental Therapeutics