Ventilatory effects of negative GABA(A) modulators in rhesus monkeys

This study examined changes in ventilation produced by negative gamma-aminobutyric acid(A) (GABA(A)) modulators in rhesus monkeys. The effects of Ro 15-4513, beta-CCE and beta-CCM were examined in four rhesus monkeys breathing air or 5% CO2 in air. When monkeys breathed CO2, minute volume (VE) and frequency (f) increased, on average, to 158 and 140% of control (air), respectively. Ro 15-4513 did not modify ventilation in monkeys breathing either gas mixture; however, beta-CCE and beta-CCM increased VE and f in monkeys breathing air to between 123 and 141% of control and had no effect on ventilation of 5% CO2. Increased ventilation produced by the negative GABA(A) modulators appeared to be maximal, because ventilation was not further enhanced when the dose was increased three-fold. Each of the three negative GABA(A) modulators reversed the decreases in ventilation produced by diazepam, suggesting that these drugs are acting at benzodiazepine receptors; however, the increased ventilation produced by beta-CCE and beta-CCM might suggest that they have more negative efficacy than Ro 15-4513. These data extend previous findings by showing that some negative GABA(A) modulators (Ro 15-4513) do not alter ventilation and further indicate that changes in ventilation can be used to evaluate efficacy differences among GABA(A) modulators.