Effect of β-carboline-3-carboxoylate-t-butyl ester on ventilatory control

β-carboline-3-carboxylate-t-butyl ester (βCCT) is the most selective antagonist for the α1β2γ2 benzodiazepine (BZ) receptor subtype which blocks anticonvulsant and antipunishment (anxiolytic) but not sedative and myorelaxant effects of diazepam. We sought to determine whether the α1β2γ2 BZ receptor subtype modulates ventilation and whether βCCT antagonizes respiratory depressant effects of BZ's. Room air (RA) ventilation and the ventilatory response to 6% & 12% CO2 were non-invasively assessed by barometric plethysmography in 30gm mice, n = 11. Plethysmograph signal amplitude (AMP), respiratory rate (RR) and minute ventilatory effort (MVE = AMP∗RR), were measured. Runs were performed pre-drug & after IP injection of saline, vehicle for βCCT, βCCT (60 mgkg), midazolam (10 mgkg), and midazolam followed by βCCT. Compared with pre-drug values, midazolam depressed MVE during RA and CO2 stimulation (% of pre-drug value: RA:57.7 ± 17.4%, 6% CO2: 53.73 ± 14.3%, 12%CO2: 69.1 ± 26.1%, p < .0001, ANOVA). Subsequent βCCT partially reversed this depression during RA conditions (72.8 ± 25.7% of pre-drug value, p < .03 compared with midazolam) and 6% CO2 stimulation (67.1 ± 10.7% of pre-drug value, p < .006 compared with midazolam) but not with 12% CO2. Thus, the α1β2γ2 BZ receptor subtype modulates ventilation and βCCT partially antagonizes respiratory depressant effects of BZ's.