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.
|Original language||English (US)|
|Number of pages||7|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - 2000|
ASJC Scopus subject areas
- Molecular Medicine