Respiratory effects of benzodiazepine-related drugs in awake rhesus monkeys

The respiratory effects of several benzodiazepine (BZ) agonists and inverse agonists were compared with those of buspirone and pentobarbital in awake rhesus monkeys. Subjects, fitted with a helmet that served as a pressure displacement plethysmograph, were studied in a ventilated, sound-attenuating chamber; ventilatory frequency, tidal volume (VT) and minute volume (VE) were determined from the plethysmograph signal. During experimental sessions monkeys inhaled either 5% carbon dioxide (CO2) mixed in air or air alone according to a fixed alternating schedule. BZ agonists (alprazolam, 0.01-1.0 mg/kg; lorazepam, 0.3-10.0 mg/kg; quazepam, 1.0-5.6 mg/kg) decreased VT and VE during both 5% CO2 and air inhalation. Pentobarbital (3.0-30.0 mg/kg) also decreased VT and VE and additionally decreased respiratory frequency in monkeys breathing 5% CO2. Two BZ inverse agonists, the beta-carbolines beta-CCE and FG 7142 (0.3-5.6 or 10.00 mg/kg), increased frequency and had no effect on VT, resulting in an increase in VE in monkeys breathing either 5% CO2 or air. The weak BZ inverse agonist CGS 8216 (0.3-5.6 mg/kg) similarly increased ventilation only in monkeys breathing air. Buspirone (0.03-0.3 mg/kg), like the beta-carbolines, increased frequency and VE and, like the BZ agonists, decreased VT. The BZ antagonist Ro15-1788 (0.1-3.0 mg/kg) had little or no effect on ventilation, but Ro15-1788 and also CGS 8216 (both at 1.0 mg/kg) attenuated the respiratory depressant effects of lorazepam or alprazolam. In turn, alprazolam (0.03-0.3 mg/kg) and quazepam (1.0-3.0 mg/kg) attenuated the respiratory stimulant effects of FG 7142.(ABSTRACT TRUNCATED AT 250 WORDS)